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1
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Ketema EB, Lopaschuk GD. The Impact of Obesity on Cardiac Energy Metabolism and Efficiency in Heart Failure With Preserved Ejection Fraction. Can J Cardiol 2025:S0828-282X(25)00099-6. [PMID: 39892611 DOI: 10.1016/j.cjca.2025.01.029] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2024] [Revised: 01/13/2025] [Accepted: 01/27/2025] [Indexed: 02/04/2025] Open
Abstract
The incidence and prevalence of heart failure with preserved ejection fraction (HFpEF) continues to rise, and now comprises more than half of all heart failure cases. There are many risk factors for HFpEF, including older age, hypertension, diabetes, dyslipidemia, sedentary behaviour, and obesity. The rising prevalence of obesity in society is a particularly important contributor to HFpEF development and severity. Obesity can adversely affect the heart, including inducing marked alterations in cardiac energy metabolism. This includes obesity-induced impairments in mitochondrial function, and an increase in fatty acid uptake and mitochondrial fatty acid β-oxidation. This increase in myocardial fatty acid metabolism is accompanied by an impaired myocardial insulin signaling and a marked decrease in glucose oxidation. This switch from glucose to fatty acid metabolism decreases cardiac efficiency and can contribute to severity of HFpEF. Increased myocardial fatty acid uptake in obesity is also associated with the accumulation of fatty acids, resulting in cardiac lipotoxicity. Obesity also results in dramatic changes in the release of adipokines, which can negatively impact cardiac function and energy metabolism. Obesity-induced increases in epicardial fat can also increase cardiac insulin resistance and negatively affect cardiac energy metabolism and HFpEF. However, optimizing cardiac energy metabolism in obese subjects may be one approach to preventing and treating HFpEF. This review discusses what is presently known about the effects of obesity on cardiac energy metabolism and insulin signaling in HFpEF. The clinical implications of obesity and energy metabolism on HFpEF are also discussed.
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Affiliation(s)
- Ezra B Ketema
- Cardiovascular Research Centre, University of Alberta, Edmonton, Canada; Department of Pediatrics, University of Alberta, Edmonton, Alberta, Canada. https://twitter.com/Ketema
| | - Gary D Lopaschuk
- Cardiovascular Research Centre, University of Alberta, Edmonton, Canada; Department of Pediatrics, University of Alberta, Edmonton, Alberta, Canada.
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2
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Valladolid-Acebes I. Hippocampal Leptin Resistance and Cognitive Decline: Mechanisms, Therapeutic Strategies and Clinical Implications. Biomedicines 2024; 12:2422. [PMID: 39594988 PMCID: PMC11591892 DOI: 10.3390/biomedicines12112422] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2024] [Revised: 10/17/2024] [Accepted: 10/17/2024] [Indexed: 11/28/2024] Open
Abstract
Background: Leptin, an adipokine essential for regulating energy balance, exerts important effects on brain function, notably within the hippocampus, a region integral to learning and memory. Leptin resistance, characterized by diminished responsiveness to elevated leptin levels, disrupts hippocampal function and exacerbates both obesity and cognitive impairments. Scope: This review critically examines how leptin resistance impairs hippocampal synaptic plasticity processes, specifically affecting long-term potentiation (LTP) and long-term depression (LTD), which are crucial for cognitive performance. Findings: Recent research highlights that leptin resistance disrupts N-methyl-D-aspartate (NMDA) receptor dynamics and hippocampal structure, leading to deficits in spatial learning and memory. Additionally, high-fat diets (HFDs), which contribute to leptin resistance, further deteriorate hippocampal function. Potential therapeutic strategies, including leptin sensitizers, show promise in mitigating brain disorders associated with leptin resistance. Complementary interventions such as caloric restriction and physical exercise also enhance leptin sensitivity and offer potential benefits to alleviating cognitive impairments. Aims of the review: This review synthesizes recent findings on the molecular pathways underlying leptin resistance and its impact on synaptic transmission and plasticity in the hippocampus. By identifying potential therapeutic targets, this work aims to provide an integrated approach for addressing cognitive deficits in obesity, ultimately improving the quality of life for affected individuals.
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Affiliation(s)
- Ismael Valladolid-Acebes
- The Rolf Luft Research Center for Diabetes and Endocrinology, Karolinska Institutet, Karolinska University Hospital L1, SE-171 76 Stockholm, Sweden
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3
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Karmazyn M, Gan XT. Molecular and Cellular Mechanisms Underlying the Cardiac Hypertrophic and Pro-Remodelling Effects of Leptin. Int J Mol Sci 2024; 25:1137. [PMID: 38256208 PMCID: PMC10816997 DOI: 10.3390/ijms25021137] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2023] [Revised: 01/10/2024] [Accepted: 01/11/2024] [Indexed: 01/24/2024] Open
Abstract
Since its initial discovery in 1994, the adipokine leptin has received extensive interest as an important satiety factor and regulator of energy expenditure. Although produced primarily by white adipocytes, leptin can be synthesized by numerous tissues including those comprising the cardiovascular system. Cardiovascular function can thus be affected by locally produced leptin via an autocrine or paracrine manner but also by circulating leptin. Leptin exerts its effects by binding to and activating specific receptors, termed ObRs or LepRs, belonging to the Class I cytokine family of receptors of which six isoforms have been identified. Although all ObRs have identical intracellular domains, they differ substantially in length in terms of their extracellular domains, which determine their ability to activate cell signalling pathways. The most important of these receptors in terms of biological effects of leptin is the so-called long form (ObRb), which possesses the complete intracellular domain linked to full cell signalling processes. The heart has been shown to express ObRb as well as to produce leptin. Leptin exerts numerous cardiac effects including the development of hypertrophy likely through a number of cell signaling processes as well as mitochondrial dynamics, thus demonstrating substantial complex underlying mechanisms. Here, we discuss mechanisms that potentially mediate leptin-induced cardiac pathological hypertrophy, which may contribute to the development of heart failure.
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Pan J, Yin J, Gan L, Xue J. Two-sided roles of adipose tissue: Rethinking the obesity paradox in various human diseases from a new perspective. Obes Rev 2023; 24:e13521. [PMID: 36349390 DOI: 10.1111/obr.13521] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/20/2022] [Revised: 08/05/2022] [Accepted: 10/17/2022] [Indexed: 11/11/2022]
Abstract
Overweight and obesity, as a result of excess fat accumulation, have become a worldwide public health issue. Recent studies have shown that obesity is closely related to many human diseases, such as cancer, cardiovascular diseases, and type 2 diabetes mellitus, in which adipose tissue plays a dual role. In addition to thermal and mechanical insulation and a critical role in energy storage and heat production, adipose tissue is also a highly plastic endocrine and signaling organ that secretes multiple bioactive molecules for inter-organ crosstalk. The phenotypic and biological changes of adipose tissue under pathological conditions, especially in obesity, increase the challenge of deciphering the positive or negative effects of adipose tissue in disease. Despite numerous studies on obesity and adipose tissue, the ambiguous role of adipose tissue on specific organs or tissues in different diseases is not fully understood, and the definite mechanisms remain obscure. In this review, we first summarize the basic biological characteristics of adipose tissue in the physiological state and the abnormal remodeling of adipose tissue during obesity. We then discuss the complex and disparate effects of obesity on various human diseases, with a particular focus on the dual roles and underlying mechanisms of adipose tissue, a quintessential player in obesity, in this process. More importantly, rethinking the causes of the "obesity paradox" phenomenon in diseases from the perspective of adipose homeostasis and dysfunction provides a novel strategy for disease treatment by intervening in fat function.
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Affiliation(s)
- Jing Pan
- Thoracic Oncology Ward, Cancer Center and State Key Laboratory of Biotherapy, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China
| | - Jianqiong Yin
- Thoracic Oncology Ward, Cancer Center and State Key Laboratory of Biotherapy, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China
| | - Lu Gan
- Research Laboratory of Emergency Medicine, Department of Emergency Medicine, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China
| | - Jianxin Xue
- Thoracic Oncology Ward, Cancer Center and State Key Laboratory of Biotherapy, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China.,Department of Radiation Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, China.,Laboratory of Clinical Cell Therapy, West China Hospital, Sichuan University, Chengdu, China
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5
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Mayer O, Bruthans J, Seidlerová J, Gelžinský J, Kučera R, Karnosová P, Mateřánková M, Wohlfahrt P, Cífková R, Filipovský J. High leptin status indicates an increased risk of mortality and heart failure in stable coronary artery disease. Nutr Metab Cardiovasc Dis 2022; 32:2137-2146. [PMID: 35843790 DOI: 10.1016/j.numecd.2022.06.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/13/2022] [Revised: 05/31/2022] [Accepted: 06/08/2022] [Indexed: 11/16/2022]
Abstract
BACKGROUND AND AIMS Leptin is an adipocyte-derived peptide involved in energy homeostasis and body weight regulation. The position of leptin in cardiovascular pathophysiology remains controversial. Some studies suggest a detrimental effect of hyperleptinemia on the cardiovascular (CV) system, while others assume the role of leptin as a neutral or even protective factor. We have explored whether high leptin affects the mortality and morbidity risk in patients with stable coronary heart disease. METHODS AND RESULTS We followed 975 patients ≥6 months after myocardial infarction or coronary revascularization in a prospective study. All-cause or cardiovascular death, non-fatal cardiovascular events (recurrent myocardial infarction, stroke, or any revascularization), and hospitalizations for heart failure (HF) we used as outcomes. High serum leptin concentrations (≥18.9 ng/mL, i.e., 4th quartile) were associated with worse survival, as well as with a higher incidence of fatal vascular events or hospitalizations for HF. Even after full adjustment for potential covariates, high leptin remained to be associated with a significantly increased 5-years risk of all-cause death [Hazard risk ratio (HRR) 2.10 (95%CIs:1.29-3.42), p < 0.003], CV death [HRR 2.65 (95%CIs:1.48-4.74), p < 0.001], and HF hospitalization [HRR 1.95 (95% CIs:1.11-3.44), p < 0.020]. In contrast, the incidence risk of non-fatal CV events was only marginally and non-significantly influenced [HRR 1.27 (95%CIs:0.76-2.13), p = 0.359]. CONCLUSIONS High leptin concentration entails an increased risk of mortality, apparently driven by fatal CV events and future worsening of HF, on top of conventional CV risk factors and the baseline status of left ventricular function.
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Affiliation(s)
- Otto Mayer
- 2nd Department of Internal Medicine, Medical Faculty of Charles University and University Hospital, Pilsen, Czech Republic; Biomedical Center, Medical Faculty of Charles University, Pilsen, Czech Republic.
| | - Jan Bruthans
- 2nd Department of Internal Medicine, Medical Faculty of Charles University and University Hospital, Pilsen, Czech Republic; Centre for Cardiovascular Prevention, First Faculty of Medicine, Charles, University and Thomayer Hospital, Prague, Czech Republic
| | - Jitka Seidlerová
- 2nd Department of Internal Medicine, Medical Faculty of Charles University and University Hospital, Pilsen, Czech Republic; Biomedical Center, Medical Faculty of Charles University, Pilsen, Czech Republic
| | - Julius Gelžinský
- 2nd Department of Internal Medicine, Medical Faculty of Charles University and University Hospital, Pilsen, Czech Republic; Biomedical Center, Medical Faculty of Charles University, Pilsen, Czech Republic
| | - Radek Kučera
- Laboratory of Immunochemical Diagnostics, University Hospital, Pilsen, Czech Republic
| | - Petra Karnosová
- 2nd Department of Internal Medicine, Medical Faculty of Charles University and University Hospital, Pilsen, Czech Republic; Biomedical Center, Medical Faculty of Charles University, Pilsen, Czech Republic
| | - Markéta Mateřánková
- 2nd Department of Internal Medicine, Medical Faculty of Charles University and University Hospital, Pilsen, Czech Republic; Biomedical Center, Medical Faculty of Charles University, Pilsen, Czech Republic
| | - Peter Wohlfahrt
- Centre for Cardiovascular Prevention, First Faculty of Medicine, Charles, University and Thomayer Hospital, Prague, Czech Republic
| | - Renata Cífková
- Centre for Cardiovascular Prevention, First Faculty of Medicine, Charles, University and Thomayer Hospital, Prague, Czech Republic
| | - Jan Filipovský
- 2nd Department of Internal Medicine, Medical Faculty of Charles University and University Hospital, Pilsen, Czech Republic; Biomedical Center, Medical Faculty of Charles University, Pilsen, Czech Republic
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Khan MM. Disrupted leptin-fatty acid biosynthesis is an early manifestation of metabolic abnormalities in schizophrenia. World J Psychiatry 2022; 12:827-842. [PMID: 35978970 PMCID: PMC9258274 DOI: 10.5498/wjp.v12.i6.827] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/31/2021] [Revised: 04/03/2022] [Accepted: 05/22/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Insulin resistance (IR) and impaired energy expenditure (IEE) are irreparable metabolic comorbidities in schizophrenia. Although mechanism(s) underlying IR and IEE remains unclear, leptin and fatty acid signaling, which has profound influence on insulin secretion/sensitivity, glucose metabolism and energy expenditure, could be disrupted. However, no association of plasma leptin with erythrocyte membrane fatty acids, body mass index (BMI), and psychotic symptoms in the same cohort of untreated patients with first-episode psychosis (FEP) or medicated patients with chronic schizophrenia (CSZ) is presented before. These studies are crucial for deciphering the role of leptin and fatty acids in the development of IR and IEE in schizophrenia. AIM To determine the association between plasma leptin, erythrocyte membrane fatty acids, particularly, saturated fatty acids (SFAs), BMI and psychotic symptoms in patients with FEP and CSZ. METHODS In this study, twenty-two drug naive patients with FEP, twenty-one CSZ patients treated with atypical antipsychotic drugs, and fourteen healthy control (CNT) subjects were analyzed. Plasma leptin was measured using sandwich mode enzyme-linked immunosorbent assay. Erythrocyte membrane SFAs were measured using ultrathin capillary gas chromatography. BMI was calculated by using the formula: weight (kg)/height (m2). Psychiatric symptoms were evaluated at baseline using brief psychiatric rating scale (BPRS), and positive and negative syndrome scale (PANSS). The total BPRS scores, positive and negative symptom scores (PANSS-PSS and PANSS-NSS, respectively) were recorded. Pearson correlation coefficient (r) analyses were performed to find the nature and strength of association between plasma leptin, PANSS scores, BMI and SFAs, particularly, palmitic acid (PA). RESULTS In patients with FEP, plasma leptin not BMI was significantly lower (P = 0.034), whereas, erythrocyte membrane SFAs were significantly higher (P < 0.005) compared to the CNT subjects. Further, plasma leptin showed negative correlation with erythrocyte membrane SFAs-PA (r = -0.4972, P = 0.001), PANSS-PSS (r = -0.4034, P = 0.028), and PANSS-NSS (r = -0.3487, P = 0.048). However, erythrocyte membrane SFAs-PA showed positive correlation with PANSS-PSS (r = 0.5844, P = 0.0034) and PANSS-NSS (r = 0.5380, P = 0.008). In CSZ patients, plasma leptin, BMI, and erythrocyte membrane SFAs, all were significantly higher (P < 0.05) compared to the CNT subjects. Plasma leptin showed positive correlation with BMI (r = 0.312, P = 0.032) but not with PANSS scores or erythrocyte membrane SFAs-PA. However, erythrocyte membrane SFAs-PA showed positive correlation with PANSS-NSS only (r = 0.4729, P = 0.031). Similar changes in the plasma leptin and erythrocyte membrane SFAs have also been reported in individuals at ultra-high risk of developing psychosis; therefore, the above findings suggest that leptin-fatty acid biosynthesis could be disrupted before the onset of psychosis in schizophrenia. CONCLUSION Disrupted leptin-fatty acid biosynthesis/signaling could be an early manifestation of metabolic comorbidities in schizophrenia. Large-scale studies are warranted to validate the above findings.
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Affiliation(s)
- Mohammad M Khan
- Laboratory of Translational Neurology and Molecular Psychiatry, Department of Biotechnology, Era's Lucknow Medical College and Hospital, and Faculty of Science, Era University, Lucknow 226003, India
- Department of Psychiatry and Health Behavior, Medical College of Georgia, Augusta University, Augusta, GA 30912, United States
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7
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Wang Y, Yu W, Li S, Guo D, He J, Wang Y. Acetyl-CoA Carboxylases and Diseases. Front Oncol 2022; 12:836058. [PMID: 35359351 PMCID: PMC8963101 DOI: 10.3389/fonc.2022.836058] [Citation(s) in RCA: 71] [Impact Index Per Article: 23.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2021] [Accepted: 02/10/2022] [Indexed: 12/28/2022] Open
Abstract
Acetyl-CoA carboxylases (ACCs) are enzymes that catalyze the carboxylation of acetyl-CoA to produce malonyl-CoA. In mammals, ACC1 and ACC2 are two members of ACCs. ACC1 localizes in the cytosol and acts as the first and rate-limiting enzyme in the de novo fatty acid synthesis pathway. ACC2 localizes on the outer membrane of mitochondria and produces malonyl-CoA to regulate the activity of carnitine palmitoyltransferase 1 (CPT1) that involves in the β-oxidation of fatty acid. Fatty acid synthesis is central in a myriad of physiological and pathological conditions. ACC1 is the major member of ACCs in mammalian, mountains of documents record the roles of ACC1 in various diseases, such as cancer, diabetes, obesity. Besides, acetyl-CoA and malonyl-CoA are cofactors in protein acetylation and malonylation, respectively, so that the manipulation of acetyl-CoA and malonyl-CoA by ACC1 can also markedly influence the profile of protein post-translational modifications, resulting in alternated biological processes in mammalian cells. In the review, we summarize our understandings of ACCs, including their structural features, regulatory mechanisms, and roles in diseases. ACC1 has emerged as a promising target for diseases treatment, so that the specific inhibitors of ACC1 for diseases treatment are also discussed.
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Affiliation(s)
- Yu Wang
- Department of Biochemistry and Molecular Biology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science of Technology, Wuhan, China
| | - Weixing Yu
- Department of Biochemistry and Molecular Biology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science of Technology, Wuhan, China
| | - Sha Li
- Department of Biochemistry and Molecular Biology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science of Technology, Wuhan, China
| | - Dingyuan Guo
- Department of Biochemistry and Molecular Biology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science of Technology, Wuhan, China
| | - Jie He
- Department of Biochemistry and Molecular Biology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science of Technology, Wuhan, China
- Department of Neurosurgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yugang Wang
- Department of Biochemistry and Molecular Biology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science of Technology, Wuhan, China
- Cell Architecture Research Center, Huazhong University of Science and Technology, Wuhan, China
- *Correspondence: Yugang Wang,
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8
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Kamareddine L, Ghantous CM, Allouch S, Al-Ashmar SA, Anlar G, Kannan S, Djouhri L, Korashy HM, Agouni A, Zeidan A. Between Inflammation and Autophagy: The Role of Leptin-Adiponectin Axis in Cardiac Remodeling. J Inflamm Res 2021; 14:5349-5365. [PMID: 34703273 PMCID: PMC8528546 DOI: 10.2147/jir.s322231] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2021] [Accepted: 08/24/2021] [Indexed: 01/05/2023] Open
Abstract
Cardiac remodeling is the process by which the heart adapts to stressful stimuli, such as hypertension and ischemia/reperfusion; it ultimately leads to heart failure upon long-term exposure. Autophagy, a cellular catabolic process that was originally considered as a mechanism of cell death in response to detrimental stimuli, is thought to be one of the main mechanisms that controls cardiac remodeling and induces heart failure. Dysregulation of the adipokines leptin and adiponectin, which plays essential roles in lipid and glucose metabolism, and in the pathophysiology of the neuroendocrine and cardiovascular systems, has been shown to affect the autophagic response in the heart and to contribute to accelerate cardiac remodeling. The obesity-associated protein leptin is a pro-inflammatory, tumor-promoting adipocytokine whose elevated levels in obesity are associated with acute cardiovascular events, and obesity-related hypertension. Adiponectin exerts anti-inflammatory and anti-tumor effects, and its reduced levels in obesity correlate with the pathogenesis of obesity-associated cardiovascular diseases. Leptin- and adiponectin-induced changes in autophagic flux have been linked to cardiac remodeling and heart failure. In this review, we describe the different molecular mechanisms of hyperleptinemia- and hypoadiponectinemia-mediated pathogenesis of cardiac remodeling and the involvement of autophagy in this process. A better understanding of the roles of leptin, adiponectin, and autophagy in cardiac functions and remodeling, and the exact signal transduction pathways by which they contribute to cardiac diseases may well lead to discovery of new therapeutic agents for the treatment of cardiovascular remodeling.
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Affiliation(s)
- Layla Kamareddine
- Department Biomedical Sciences, College of Health Sciences, QU Health, Qatar University, Doha, Qatar
- Biomedical and Pharmaceutical Research Unit, QU Health, Qatar University, Doha, Qatar
- Biomedical Research Center, Qatar University, Doha, Qatar
| | - Crystal M Ghantous
- Department of Nursing and Health Sciences, Faculty of Nursing and Health Sciences, Notre Dame University-Louaize, Keserwan, Lebanon
| | - Soumaya Allouch
- Department of Basic Sciences, College of Medicine, QU Health, Qatar University, Doha, Qatar
| | - Sarah A Al-Ashmar
- Biomedical and Pharmaceutical Research Unit, QU Health, Qatar University, Doha, Qatar
- Department of Basic Sciences, College of Medicine, QU Health, Qatar University, Doha, Qatar
| | - Gulsen Anlar
- Biomedical and Pharmaceutical Research Unit, QU Health, Qatar University, Doha, Qatar
- Department of Basic Sciences, College of Medicine, QU Health, Qatar University, Doha, Qatar
| | - Surya Kannan
- Biomedical and Pharmaceutical Research Unit, QU Health, Qatar University, Doha, Qatar
- Department of Basic Sciences, College of Medicine, QU Health, Qatar University, Doha, Qatar
| | - Laiche Djouhri
- Biomedical and Pharmaceutical Research Unit, QU Health, Qatar University, Doha, Qatar
- Department of Basic Sciences, College of Medicine, QU Health, Qatar University, Doha, Qatar
| | - Hesham M Korashy
- Biomedical and Pharmaceutical Research Unit, QU Health, Qatar University, Doha, Qatar
- Department of Pharmaceutical Sciences, College of Pharmacy, QU Health, Qatar University, Doha, Qatar
| | - Abdelali Agouni
- Biomedical and Pharmaceutical Research Unit, QU Health, Qatar University, Doha, Qatar
- Department of Pharmaceutical Sciences, College of Pharmacy, QU Health, Qatar University, Doha, Qatar
| | - Asad Zeidan
- Biomedical and Pharmaceutical Research Unit, QU Health, Qatar University, Doha, Qatar
- Department of Basic Sciences, College of Medicine, QU Health, Qatar University, Doha, Qatar
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9
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Pereira S, Cline DL, Glavas MM, Covey SD, Kieffer TJ. Tissue-Specific Effects of Leptin on Glucose and Lipid Metabolism. Endocr Rev 2021; 42:1-28. [PMID: 33150398 PMCID: PMC7846142 DOI: 10.1210/endrev/bnaa027] [Citation(s) in RCA: 117] [Impact Index Per Article: 29.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/06/2020] [Indexed: 12/18/2022]
Abstract
The discovery of leptin was intrinsically associated with its ability to regulate body weight. However, the effects of leptin are more far-reaching and include profound glucose-lowering and anti-lipogenic effects, independent of leptin's regulation of body weight. Regulation of glucose metabolism by leptin is mediated both centrally and via peripheral tissues and is influenced by the activation status of insulin signaling pathways. Ectopic fat accumulation is diminished by both central and peripheral leptin, an effect that is beneficial in obesity-associated disorders. The magnitude of leptin action depends upon the tissue, sex, and context being examined. Peripheral tissues that are of particular relevance include the endocrine pancreas, liver, skeletal muscle, adipose tissues, immune cells, and the cardiovascular system. As a result of its potent metabolic activity, leptin is used to control hyperglycemia in patients with lipodystrophy and is being explored as an adjunct to insulin in patients with type 1 diabetes. To fully understand the role of leptin in physiology and to maximize its therapeutic potential, the mechanisms of leptin action in these tissues needs to be further explored.
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Affiliation(s)
- Sandra Pereira
- Department of Cellular and Physiological Sciences, University of British Columbia, Vancouver, Canada
| | - Daemon L Cline
- Department of Cellular and Physiological Sciences, University of British Columbia, Vancouver, Canada
| | - Maria M Glavas
- Department of Cellular and Physiological Sciences, University of British Columbia, Vancouver, Canada
| | - Scott D Covey
- Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, Canada
| | - Timothy J Kieffer
- Department of Cellular and Physiological Sciences, University of British Columbia, Vancouver, Canada.,Department of Surgery, University of British Columbia, Vancouver, Canada.,School of Biomedical Engineering, University of British Columbia, Vancouver, Canada
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10
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Gava FN, da Silva AA, Dai X, Harmancey R, Ashraf S, Omoto ACM, Salgado MC, Moak SP, Li X, Hall JE, do Carmo JM. Restoration of Cardiac Function After Myocardial Infarction by Long-Term Activation of the CNS Leptin-Melanocortin System. JACC Basic Transl Sci 2021; 6:55-70. [PMID: 33532666 PMCID: PMC7838051 DOI: 10.1016/j.jacbts.2020.11.007] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/13/2020] [Revised: 11/12/2020] [Accepted: 11/12/2020] [Indexed: 12/17/2022]
Abstract
Leptin protects against progression to heart failure after myocardial infarction. This beneficial effect requires activation of the brain melanocortin system. Stimulation of brain MC4R recapitulates the cardiac protective effects of leptin. Leptin-MC4R activation improves cardiac substrate oxidation and mitochondrial function. It also improves Ca2+ coupling and contractile function in viable cardiomyocytes after MI. Heart failure has a high mortality rate, and current therapies offer limited benefits. The authors demonstrate that activation of the central nervous system leptin-melanocortin pathway confers remarkable protection against progressive heart failure following severe myocardial infarction. The beneficial cardiac-protective actions of leptin require activation of brain melanocortin-4 receptors and elicit improvements in cardiac substrate oxidation, cardiomyocyte contractility, Ca2+ coupling, and mitochondrial efficiency. These findings highlight a potentially novel therapeutic approach for myocardial infarction and heart failure.
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Key Words
- AMPK, adenosine monophosphate–activated protein kinase
- BP, blood pressure
- CNS, central nervous system
- HF, heart failure
- HR, heart rate
- ICV, intracerebroventricular
- LV, left ventricular
- MC4R
- MC4R, melanocortin-4 receptor
- MI, myocardial infarction
- MTII, melanotan II
- appetite
- blood pressure
- cardiac metabolism
- heart failure
- mTOR, mechanistic target of rapamycin
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Affiliation(s)
- Fabio N Gava
- Department of Physiology and Biophysics and Mississippi Center for Obesity Research, Cardiovascular-Renal Research Center, University of Mississippi Medical Center, Jackson, Mississippi, USA.,Department of Veterinary Clinics, Londrina State University, Parana, Brazil
| | - Alexandre A da Silva
- Department of Physiology and Biophysics and Mississippi Center for Obesity Research, Cardiovascular-Renal Research Center, University of Mississippi Medical Center, Jackson, Mississippi, USA
| | - Xuemei Dai
- Department of Physiology and Biophysics and Mississippi Center for Obesity Research, Cardiovascular-Renal Research Center, University of Mississippi Medical Center, Jackson, Mississippi, USA
| | - Romain Harmancey
- Department of Physiology and Biophysics and Mississippi Center for Obesity Research, Cardiovascular-Renal Research Center, University of Mississippi Medical Center, Jackson, Mississippi, USA
| | - Sadia Ashraf
- Department of Physiology and Biophysics and Mississippi Center for Obesity Research, Cardiovascular-Renal Research Center, University of Mississippi Medical Center, Jackson, Mississippi, USA
| | - Ana C M Omoto
- Department of Physiology and Biophysics and Mississippi Center for Obesity Research, Cardiovascular-Renal Research Center, University of Mississippi Medical Center, Jackson, Mississippi, USA.,Department of Physiology, University of Sao Paulo, Ribeirao Preto, Sao Paulo, Brazil
| | - Mateus C Salgado
- Department of Physiology and Biophysics and Mississippi Center for Obesity Research, Cardiovascular-Renal Research Center, University of Mississippi Medical Center, Jackson, Mississippi, USA.,Centro Universitário Barão de Mauá, Ribeirão Preto, São Paulo, Brazil
| | - Sydney P Moak
- Department of Physiology and Biophysics and Mississippi Center for Obesity Research, Cardiovascular-Renal Research Center, University of Mississippi Medical Center, Jackson, Mississippi, USA
| | - Xuan Li
- Department of Physiology and Biophysics and Mississippi Center for Obesity Research, Cardiovascular-Renal Research Center, University of Mississippi Medical Center, Jackson, Mississippi, USA
| | - John E Hall
- Department of Physiology and Biophysics and Mississippi Center for Obesity Research, Cardiovascular-Renal Research Center, University of Mississippi Medical Center, Jackson, Mississippi, USA
| | - Jussara M do Carmo
- Department of Physiology and Biophysics and Mississippi Center for Obesity Research, Cardiovascular-Renal Research Center, University of Mississippi Medical Center, Jackson, Mississippi, USA
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11
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Figueroa-Juárez E, Noriega LG, Pérez-Monter C, Alemán G, Hernández-Pando R, Correa-Rotter R, Ramírez V, Tovar AR, Torre-Villalvazo I, Tovar-Palacio C. The Role of the Unfolded Protein Response on Renal Lipogenesis in C57BL/6 Mice. Biomolecules 2021; 11:73. [PMID: 33430288 PMCID: PMC7825661 DOI: 10.3390/biom11010073] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2020] [Revised: 12/27/2020] [Accepted: 01/01/2021] [Indexed: 11/25/2022] Open
Abstract
Renal injury observed in several pathologies has been associated with lipid accumulation in the kidney. While it has been suggested that the accumulation of renal lipids depends on free fatty acids released from adipose tissue, it is not known whether in situ renal lipogenesis due to endoplasmic reticulum (ER) stress contributes to kidney injury. The aim of the present study was to elucidate the role of pharmacological ER stress in renal structure and function and its effect on renal lipid metabolism of C57BL/6 mice. ER stress increased serum creatinine and induced kidney structural abnormalities. Tunicamycin-administered mice developed hyperinsulinemia, augmented lipolysis and increased circulating leptin and adiponectin. Renal unfolded protein response (UPR) gene expression markers, the lipogenic transcription factor SREBP1 and the phosphorylation of eIF2α increased 8 h after tunicamycin administration. At 24 h, an increase in BiP protein content was accompanied by a reduction in p-eIF2α and increased SREBP-1 and FASn protein content, in addition to a significant increase in triglyceride content and a reduction in AMPK. Thus, ER stress induces in situ lipid synthesis, leading to renal lipid accumulation and functional alterations. Future pharmacological and/or dietary strategies must target renal ER stress to prevent kidney damage and the progression of metabolic diseases.
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Affiliation(s)
- Elizabeth Figueroa-Juárez
- Metabolic Research Laboratories, Institute of Metabolic Science, Addenbrooke’s Hospital, University of Cambridge, Cambridge CB2 1TN, UK;
- Nefrología y Metabolismo Mineral, Instituto Nacional de Ciencias Médicas y Nutrición, Salvador CDMX 14080, Mexico;
| | - Lilia G. Noriega
- Fisiología de la Nutrición, Instituto Nacional de Ciencias Médicas y Nutrición, Salvador CDMX 14080, Mexico; (L.G.N.); (G.A.); (A.R.T.)
| | - Carlos Pérez-Monter
- Gastroenterología, Instituto Nacional de Ciencias Médicas y Nutrición, Salvador CDMX 14080, Mexico;
| | - Gabriela Alemán
- Fisiología de la Nutrición, Instituto Nacional de Ciencias Médicas y Nutrición, Salvador CDMX 14080, Mexico; (L.G.N.); (G.A.); (A.R.T.)
| | - Rogelio Hernández-Pando
- Patología Experimental, Instituto Nacional de Ciencias Médicas y Nutrición, Salvador CDMX 14080, Mexico;
| | - Ricardo Correa-Rotter
- Nefrología y Metabolismo Mineral, Instituto Nacional de Ciencias Médicas y Nutrición, Salvador CDMX 14080, Mexico;
| | - Victoria Ramírez
- Cirugía Experimental, Instituto Nacional de Ciencias Médicas y Nutrición, Salvador CDMX 14080, Mexico;
| | - Armando R. Tovar
- Fisiología de la Nutrición, Instituto Nacional de Ciencias Médicas y Nutrición, Salvador CDMX 14080, Mexico; (L.G.N.); (G.A.); (A.R.T.)
| | - Iván Torre-Villalvazo
- Fisiología de la Nutrición, Instituto Nacional de Ciencias Médicas y Nutrición, Salvador CDMX 14080, Mexico; (L.G.N.); (G.A.); (A.R.T.)
| | - Claudia Tovar-Palacio
- División de Nutrición, Instituto Nacional de Ciencias Médicas y Nutrición, Salvador CDMX 14080, Mexico
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12
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Fatty acid synthesis and cancer: Aberrant expression of the ACACA and ACACB genes increases the risk for cancer. Meta Gene 2020. [DOI: 10.1016/j.mgene.2020.100798] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/01/2023] Open
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13
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Leptin mediate central obesity on the severity of cardiovascular autonomic neuropathy in well-controlled type 2 diabetes and prediabetes. J Transl Med 2020; 18:396. [PMID: 33076921 PMCID: PMC7574496 DOI: 10.1186/s12967-020-02559-7] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2020] [Accepted: 10/03/2020] [Indexed: 01/10/2023] Open
Abstract
BACKGROUND Evidences support the view that central obesity is an independently cardiovascular risk. It is thought that leptin contributes to autonomic dysfunction and cardiovascular risks in type 1 and type 2 diabetes mellitus (T1DM and T2DM). This raises the possibility that leptin might mediate the relationship between central obesity and the severity of cardiovascular autonomic neuropathy (CAN) in patients with well-controlled T2DM and prediabetes. METHODS The complete cardiovascular reflex tests and biomarkers were assessed for each patient. The severity of CAN was assessed using composite autonomic scoring scale (CASS). A single-level three-variable mediation model was used to investigate the possible relationships among central obesity [as indicated by waist circumference (WC)], leptin level, and severity of CAN (as indicated by CASS value). RESULTS A total of 107 patients were included in this study: 90 with diabetes and 17 with prediabetes. The results demonstrate that increased WC is associated with increased severity of CAN (r = 0.242, P = 0.017). We further discovered that leptin level is positively correlated with WC (r = 0.504, P < 0.0001) and the CASS value (r = 0.36, P < 0.0001). Further mediation analysis shows that leptin level serves as mediators between higher WC and higher CASS. CONCLUSIONS Our results highlighted the relationship among leptin, central obesity, and severity of CAN. As the leptin level serves as mediator between central obesity and severity of CAN, a longitudinal study is needed to confirm that control of WC can decrease leptin levels and can be effective in reducing CAN progression.
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14
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Mao S, Zhang X, Chen M, Wang C, Chen Q, Guo L, Zhang M, Hinek A. Beneficial Effects of Baduanjin Exercise on Left Ventricular Remodelling in Patients after Acute Myocardial Infarction: an Exploratory Clinical Trial and Proteomic Analysis. Cardiovasc Drugs Ther 2020; 35:21-32. [PMID: 32761487 DOI: 10.1007/s10557-020-07047-0] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 07/28/2020] [Indexed: 12/12/2022]
Abstract
BACKGROUND The beneficial effects of physical exercise on cardiac remodelling improvement after myocardial infarction have already been suggested. However, the results of previous clinical trials have not been consistent. Moreover, the putative molecular mechanisms leading to the clinically observed effects of physical exercise still remain elusive. AIM We aimed to evaluate whether the well-defined and strictly controlled traditional Chinese Qigong Baduanjin exercise (BE) would attenuate the adverse left ventricular (LV) remodelling in patients with ST-elevation myocardial infarction (STEMI). METHODS A total of 110 clinically stable STEMI patients, following successful revascularization of their infarcted coronary arteries, were randomized and enrolled in two groups: 56 were subjected to a 12-week BE-based cardiac rehabilitation programme (BE group), and the remaining 54 were exposed to the usual physical exercise (control group) for the same time period. The primary outcome was the change from baseline to 6 months in the echocardiographic LV end-diastolic volume index (ΔLVEDVi). Proteomic analysis was also performed to uncover associated mechanisms. RESULTS Compared with the control group, the BE group showed significantly lower ΔLVEDVi (-5.1 ± 1.1 vs. 0.3 ± 1.2 mL/m2, P < 0.01). Proteomic analysis revealed BE-induced variations in the expression of 80 proteins linked to regulation the of metabolic process, immune process, and extracellular matrix reorganization. Furthermore, correlation analyses between the validated serum proteomes and primary endpoint demonstrated a positive association between ΔLVEDVi and MMP-9 expression, but a negative correlation between ΔLVEDVi and CXCL1 expression. CONCLUSION This is the first study indicating that BE in STEMI patients can alleviate adverse LV remodelling associated with beneficial energy metabolism adaptation, inflammation curbing, and extracellular matrix organization adjustment.
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Affiliation(s)
- Shuai Mao
- State Key Laboratory of Dampness Syndrome of Chinese Medicine, The Second Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou, 510405, China.,Department of Critical Care Medicine, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, 510120, China.,Translational Medicine, Hospital for Sick Children, Toronto, M5G 0A4, Canada
| | - Xiaoxuan Zhang
- State Key Laboratory of Dampness Syndrome of Chinese Medicine, The Second Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou, 510405, China.,Department of Critical Care Medicine, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, 510120, China
| | - Minggui Chen
- State Key Laboratory of Dampness Syndrome of Chinese Medicine, The Second Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou, 510405, China.,Department of Critical Care Medicine, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, 510120, China
| | - Chuyang Wang
- Biological Resource Center, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, 510120, China
| | - Qubo Chen
- Biological Resource Center, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, 510120, China
| | - Liheng Guo
- State Key Laboratory of Dampness Syndrome of Chinese Medicine, The Second Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou, 510405, China.,Department of Critical Care Medicine, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, 510120, China
| | - Minzhou Zhang
- State Key Laboratory of Dampness Syndrome of Chinese Medicine, The Second Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou, 510405, China. .,Department of Critical Care Medicine, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, 510120, China.
| | - Aleksander Hinek
- Translational Medicine, Hospital for Sick Children, Toronto, M5G 0A4, Canada
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15
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Imerbtham T, Thitiwuthikiat P, Jongjitwimol J, Nuamchit T, Yingchoncharoen T, Siriwittayawan D. Leptin Levels are Associated with Subclinical Cardiac Dysfunction in Obese Adolescents. Diabetes Metab Syndr Obes 2020; 13:925-933. [PMID: 32273744 PMCID: PMC7108875 DOI: 10.2147/dmso.s245048] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/13/2020] [Accepted: 03/11/2020] [Indexed: 12/24/2022] Open
Abstract
PURPOSE The purposes of this study were to use speckle tracking echocardiography to confirm the influence of obesity on cardiac functions and to assess their relationships with leptin and uric acid levels in obese adolescents. METHODS Eighty-one participants aged 16-19 years were recruited and classified as either non-obese (n = 30) or obese (n = 51). Global longitudinal strain (GLS), leptin and uric acid levels for each group were assessed and compared. The data from obese participants were then compared based on their leptin levels and analyzed for correlation using regression analysis. RESULTS The obese group had significantly lower absolute GLS compared to the non-obese group (19.10 ± 0.30 versus 21.10 ± 0.30%, p < 0.001). In obese group, subclinical cardiac dysfunction was worse in the hyperleptinemic group than that of the normoleptinemic group (p = 0.03). Multivariate regression analysis showed that leptin and triglyceride levels were negatively associated with absolute GLS. Leptin could predict the absolute GLS with β = -0.35 (p = 0.02). CONCLUSION Subclinical left ventricular systolic dysfunction was found in obese adolescents, while GLS was worse in the hyperleptinemic subjects. Leptin, but not uric acid, levels were associated with a worsening of GLS.
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Affiliation(s)
- Thamonwan Imerbtham
- Department of Cardio-Thoracic Technology, Faculty of Allied Health Sciences, Naresuan University, Phitsanulok, Thailand
| | - Piyanuch Thitiwuthikiat
- Department of Cardio-Thoracic Technology, Faculty of Allied Health Sciences, Naresuan University, Phitsanulok, Thailand
| | - Jirapas Jongjitwimol
- Department of Medical Technology, Faculty of Allied Health Sciences, Naresuan University, Phitsanulok, Thailand
| | - Teonchit Nuamchit
- Department of Cardio-Thoracic Technology, Faculty of Allied Health Sciences, Naresuan University, Phitsanulok, Thailand
| | | | - Duangduan Siriwittayawan
- Department of Cardio-Thoracic Technology, Faculty of Allied Health Sciences, Naresuan University, Phitsanulok, Thailand
- Correspondence: Duangduan Siriwittayawan Department of Cardio-Thoracic Technology, Faculty of Allied Health Sciences, Naresuan University, Phitsanulok65000, ThailandTel +66 55 966 417Fax +66 55 966 234 Email
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16
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Altamimi TR, Gao S, Karwi QG, Fukushima A, Rawat S, Wagg CS, Zhang L, Lopaschuk GD. Adropin regulates cardiac energy metabolism and improves cardiac function and efficiency. Metabolism 2019; 98:37-48. [PMID: 31202835 DOI: 10.1016/j.metabol.2019.06.005] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/09/2019] [Revised: 05/17/2019] [Accepted: 06/07/2019] [Indexed: 02/06/2023]
Abstract
BACKGROUND Impaired cardiac insulin signalling and high cardiac fatty acid oxidation rates are characteristics of conditions of insulin resistance and diabetic cardiomyopathies. The potential role of liver-derived peptides such as adropin in mediating these changes in cardiac energy metabolism is unclear, despite the fact that in skeletal muscle adropin can preferentially promote glucose metabolism and improve insulin sensitivity. OBJECTIVES To determine the influence of adropin on cardiac energy metabolism, insulin signalling and cardiac efficiency. METHODS C57Bl/6 mice were injected with either vehicle or a secretable form of adropin (450 nmol/kg, i.p.) three times over a 24-h period. The mice were fasted to accentuate the differences between animals in adropin plasma levels before their hearts were isolated and perfused using a working heart system. In addition, direct addition of adropin to the perfusate of ex vivo hearts isolated from non-fasting mice was utilized to investigate the acute effects of the peptide on heart metabolism and ex vivo function. RESULTS In contrast to the observed fasting-induced predominance of fatty acid oxidation as a source of ATP production in control hearts, insulin inhibition of fatty acid oxidation was preserved by adropin treatment. Adropin-treated mouse hearts also showed a higher cardiac work, which was accompanied by improved cardiac efficiency and enhanced insulin signalling compared to control hearts. Interestingly, acute adropin administration to isolated working hearts also resulted in an inhibition of fatty acid oxidation, accompanied by a robust stimulation of glucose oxidation compared to vehicle-treated hearts. Adropin also increased activation of downstream cardiac insulin signalling. Moreover, both in vivo and ex vivo treatment protocols induced a reduction in the inhibitory phosphorylation of pyruvate dehydrogenase (PDH), the major enzyme of glucose oxidation, and the protein levels of the responsible kinase PDH kinase 4 and the insulin-signalling inhibitory phosphorylation of JNK (p-T183/Y185) and IRS-1 (p-S307), suggesting acute receptor- and/or post-translational modification-mediated mechanisms. CONCLUSIONS These results demonstrate that adropin has important effects on energy metabolism in the heart and may be a putative candidate for the treatment of cardiac disease associated with impaired insulin sensitivity.
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Affiliation(s)
- Tariq R Altamimi
- Cardiovascular Research Centre, Department of Pediatrics, 423 Heritage Medical Research Building, University of Alberta, Edmonton, Alberta T6G 2S2, Canada
| | - Su Gao
- Cardiovascular Research Centre, Department of Pediatrics, 423 Heritage Medical Research Building, University of Alberta, Edmonton, Alberta T6G 2S2, Canada
| | - Qutuba G Karwi
- Cardiovascular Research Centre, Department of Pediatrics, 423 Heritage Medical Research Building, University of Alberta, Edmonton, Alberta T6G 2S2, Canada; Department of Pharmacology, College of Medicine, University of Diyala, Diyala, Iraq
| | - Arata Fukushima
- Department of Cardiovascular Medicine, Faculty of Medicine, Graduate School of Medicine, Hokkaido University, Kita-15, Nishi-7, Kita-ku, Sapporo 060-8638, Japan
| | - Sonia Rawat
- Cardiovascular Research Centre, Department of Pediatrics, 423 Heritage Medical Research Building, University of Alberta, Edmonton, Alberta T6G 2S2, Canada
| | - Cory S Wagg
- Cardiovascular Research Centre, Department of Pediatrics, 423 Heritage Medical Research Building, University of Alberta, Edmonton, Alberta T6G 2S2, Canada
| | - Liyan Zhang
- Cardiovascular Research Centre, Department of Pediatrics, 423 Heritage Medical Research Building, University of Alberta, Edmonton, Alberta T6G 2S2, Canada
| | - Gary D Lopaschuk
- Cardiovascular Research Centre, Department of Pediatrics, 423 Heritage Medical Research Building, University of Alberta, Edmonton, Alberta T6G 2S2, Canada.
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17
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Saleem Mir M, Maqbool Darzi M, Musadiq Khan H, Ahmad Kamil S, Hassan Sofi A, Ahmad Wani S. Pathomorphological effects of Alloxan induced acute hypoglycaemia in rabbits. ALEXANDRIA JOURNAL OF MEDICINE 2019. [DOI: 10.1016/j.ajme.2013.03.007] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Affiliation(s)
- Masood Saleem Mir
- Division of Veterinary Pathology, F.V.Sc. & A.H. , Sher-e-Kashmir University of Agricultural Sciences and Technology of Kashmir , Shuhama, Alusteng , Kashmir (J&K), 190 006, India
| | - Mohammad Maqbool Darzi
- Division of Veterinary Pathology, F.V.Sc. & A.H. , Sher-e-Kashmir University of Agricultural Sciences and Technology of Kashmir , Shuhama, Alusteng , Kashmir (J&K), 190 006, India
| | - Hilal Musadiq Khan
- MRCSG, F.V.Sc. & A.H, Sher-e-Kashmir University of Agricultural Sciences and Technology of Kashmir , Shuhama, Alusteng , Kashmir (J&K), 190 006, India
| | - Shayaib Ahmad Kamil
- Division of Veterinary Pathology, F.V.Sc. & A.H. , Sher-e-Kashmir University of Agricultural Sciences and Technology of Kashmir , Shuhama, Alusteng , Kashmir (J&K), 190 006, India
| | - Asif Hassan Sofi
- Division of LPT, F.V.Sc. & A.H , Sher-e-Kashmir University of Agricultural Sciences and Technology of Kashmir , Shuhama, Alusteng , Kashmir (J&K), 190 006, India
| | - Sarfraz Ahmad Wani
- Division of LPT, F.V.Sc. & A.H , Sher-e-Kashmir University of Agricultural Sciences and Technology of Kashmir , Shuhama, Alusteng , Kashmir (J&K), 190 006, India
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18
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Cortese L, Terrazzano G, Pelagalli A. Leptin and Immunological Profile in Obesity and Its Associated Diseases in Dogs. Int J Mol Sci 2019; 20:2392. [PMID: 31091785 PMCID: PMC6566566 DOI: 10.3390/ijms20102392] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2019] [Revised: 05/06/2019] [Accepted: 05/08/2019] [Indexed: 12/29/2022] Open
Abstract
Growing scientific evidence has unveiled increased incidences of obesity in domestic animals and its influence on a plethora of associated disorders. Leptin, an adipokine regulating body fat mass, represents a key molecule in obesity, able to modulate immune responses and foster chronic inflammatory response in peripheral tissues. High levels of cytokines and inflammatory markers suggest an association between inflammatory state and obesity in dogs, highlighting the parallelism with humans. Canine obesity is a relevant disease always accompanied with several health conditions such as inflammation, immune-dysregulation, insulin resistance, pancreatitis, orthopaedic disorders, cardiovascular disease, and neoplasia. However, leptin involvement in many disease processes in veterinary medicine is poorly understood. Moreover, hyperleptinemia as well as leptin resistance occur with cardiac dysfunction as a consequence of altered cardiac mitochondrial metabolism in obese dogs. Similarly, leptin dysregulation seems to be involved in the pancreatitis pathophysiology. This review aims to examine literature concerning leptin and immunological status in obese dogs, in particular for the aspects related to obesity-associated diseases.
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Affiliation(s)
- Laura Cortese
- Department of Veterinary Medicine and Animal Productions, University of Naples Federico II, 80137 Naples, Italy.
| | - Giuseppe Terrazzano
- Department of Science, University of Basilicata, 85100 Potenza, Italy.
- Department of Translational Medical Sciences, University of Naples Federico II, 80131 Naples, Italy.
| | - Alessandra Pelagalli
- Department of Advanced Biomedical Sciences, University of Naples Federico II, 80131 Naples, Italy.
- Institute of Biostructures and Bioimages (IBB), National Research Council (CNR), 80131 Naples, Italy.
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19
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Karsono AH, Tandrasasmita OM, Tjandrawinata RR. Bioactive fraction from Lagerstroemia speciosa leaves (DLBS3733) reduces fat droplet by inhibiting adipogenesis and lipogenesis. J Exp Pharmacol 2019; 11:39-51. [PMID: 31118835 PMCID: PMC6507403 DOI: 10.2147/jep.s181642] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2018] [Accepted: 03/05/2019] [Indexed: 12/18/2022] Open
Abstract
Background: Obesity has become a risk factor for metabolic diseases. One of the cellular characteristics of obesity is the occurrence of adipose cells hyperplasia. Lagerstroemia speciosa is a plant which has been used for the treatment of diabetes. Furthermore, some studies also indicated that L. speciosa possesses antiobesity activity. Its antiobesity activity was examined in the present study through adipogenesis, lipogenesis, and lipolysis pathways. Aim: DLBS3733, a bioactive fraction of L. speciosa, was explored for its potential benefits to alter obesity through adipogenesis and lipogenesis inhibition and lipolysis induction activity. Materials and methods: This study was performed using 3T3-L1 cells. mRNA level and protein expressions related to adipogenesis, lipogenesis, and lipolysis pathways were assayed in this study. Results: Antiadipogenic effects of DLBS3733 (15 µg/mL) were found to be mediated by a significant downregulation of mRNA level of multicomponents involved in adipogenesis which include C/EBPα (CCAAT/enhancer-binding protein alpha) and PPAR-γ (peroxisome proliferator-activated receptor gamma) by 75% and 80.1% (p<0.05), respectively. DLBS3733 was found to inhibit lipogenesis, as shown by the significant reductions of adiponectin excretion and mRNA level of fatty acid synthase, SREBP (sterol regulatory element-binding protein), and ACC-β (Acetyl-CoA carboxylase) by 44.7%, 70.9%, and 83.1%, respectively (p<0.05). In addition, DLBS3733 was found to inhibit fat droplets accumulation in the cells in a dose-dependent manner through Oil-Red O staining. pAMPK protein was upregulated by 75% and ACC-β was downregulated by 88% (p<0.05) which indicates the reduction of lipid synthesis. Meanwhile, DLBS3733 showed an insignificant effect on adipose triglyceride lipase, hormone-sensitive lipase, and carnitine palmitoyl-CoA transferase-1 which indicate that DLBS3733 does not induce lipolysis. Conclusion: These results demonstrate the inhibitory activity of DLBS3733 on adipogenesis and lipogenesis. DLBS3733 may provide an effective and potential benefit in the prevention of obesity.
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Affiliation(s)
- Agung Heru Karsono
- Section of Molecular Pharmacology, Department of Research Innovation and Invention, Dexa Laboratories of Biomolecular Sciences, Dexa Medica, Cikarang, West Java, Indonesia
| | - Olivia Mayasari Tandrasasmita
- Section of Molecular Pharmacology, Department of Research Innovation and Invention, Dexa Laboratories of Biomolecular Sciences, Dexa Medica, Cikarang, West Java, Indonesia
| | - Raymond Rubianto Tjandrawinata
- Section of Molecular Pharmacology, Department of Research Innovation and Invention, Dexa Laboratories of Biomolecular Sciences, Dexa Medica, Cikarang, West Java, Indonesia
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20
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In vitro effect of leptin on human cardiac contractility. J Nutr Sci 2019; 8:e12. [PMID: 31019683 PMCID: PMC6465679 DOI: 10.1017/jns.2019.6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2018] [Revised: 02/13/2019] [Accepted: 02/18/2019] [Indexed: 11/12/2022] Open
Abstract
Leptin, a hormone produced by adipose tissue, has been linked to many regulatory pathways. Its role in the complex relationship between obesity and CVD is not yet clear. The aim of the present study was to evaluate whether leptin interferes directly with cardiac function regulation, altering its contractile force character, and hence contributing to different pathological processes. Muscle samples were obtained from human atrial myocardium. Each trial included two samples from the same patient. They were simultaneously electrically stimulated under sustained perfusion to perform isometric contractions. One sample was treated with a high concentration of human recombinant leptin (1 µg/ml). The other was treated with placebo and served as a control. The exhibited contraction forces (CF) and the contraction duration (CD) after 20 min of treatment were normalised by dividing them by the values before the treatment and reported as a percentage. A total of ten successful trials were conducted. Exposure to leptin did not yield a statistically significant variation in both CF and CF. In the treatment group, CF% measured 108 (95 % CI 91, 125) % and CD% measured 95 (95 % CI 90, 101) % after 20 min. In the control group, CF% measured 105 (90 % CI 84, 126) % and CD% measured 92 (95 % CI 80, 105) % after 20 min. We concluded that leptin does not alter the contractile character of human atrial tissues, even in supraphysiological dosage. These results suggest that leptin does not play a role in short-term cardiac regulation.
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21
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Govindarajulu M, Pinky PD, Bloemer J, Ghanei N, Suppiramaniam V, Amin R. Signaling Mechanisms of Selective PPAR γ Modulators in Alzheimer's Disease. PPAR Res 2018; 2018:2010675. [PMID: 30420872 PMCID: PMC6215547 DOI: 10.1155/2018/2010675] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2018] [Revised: 08/31/2018] [Accepted: 09/13/2018] [Indexed: 01/22/2023] Open
Abstract
Alzheimer's disease (AD) is a chronic neurodegenerative disease characterized by abnormal protein accumulation, synaptic dysfunction, and cognitive impairment. The continuous increase in the incidence of AD with the aged population and mortality rate indicates the urgent need for establishing novel molecular targets for therapeutic potential. Peroxisome proliferator-activated receptor gamma (PPARγ) agonists such as rosiglitazone and pioglitazone reduce amyloid and tau pathologies, inhibit neuroinflammation, and improve memory impairments in several rodent models and in humans with mild-to-moderate AD. However, these agonists display poor blood brain barrier permeability resulting in inadequate bioavailability in the brain and thus requiring high dosing with chronic time frames. Furthermore, these dosing levels are associated with several adverse effects including increased incidence of weight gain, liver abnormalities, and heart failure. Therefore, there is a need for identifying novel compounds which target PPARγ more selectively in the brain and could provide therapeutic benefits without a high incidence of adverse effects. This review focuses on how PPARγ agonists influence various pathologies in AD with emphasis on development of novel selective PPARγ modulators.
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Affiliation(s)
- Manoj Govindarajulu
- Department of Drug Discovery and Development, Harrison School of Pharmacy, Auburn University, Auburn, AL, USA
| | - Priyanka D. Pinky
- Department of Drug Discovery and Development, Harrison School of Pharmacy, Auburn University, Auburn, AL, USA
| | - Jenna Bloemer
- Department of Drug Discovery and Development, Harrison School of Pharmacy, Auburn University, Auburn, AL, USA
| | - Nila Ghanei
- Department of Drug Discovery and Development, Harrison School of Pharmacy, Auburn University, Auburn, AL, USA
| | - Vishnu Suppiramaniam
- Department of Drug Discovery and Development, Harrison School of Pharmacy, Auburn University, Auburn, AL, USA
- Center for Neuroscience, Auburn University, Auburn, AL, USA
| | - Rajesh Amin
- Department of Drug Discovery and Development, Harrison School of Pharmacy, Auburn University, Auburn, AL, USA
- Center for Neuroscience, Auburn University, Auburn, AL, USA
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22
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Mora C, Pintado C, Rubio B, Mazuecos L, López V, Fernández A, Salamanca A, Bárcena B, Fernández-Agulló T, Arribas C, Gallardo N, Andrés A. Central leptin regulates heart lipid content by selectively increasing PPAR β/δ expression. J Endocrinol 2018; 236:43-56. [PMID: 29109080 DOI: 10.1530/joe-17-0554] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/06/2017] [Accepted: 11/06/2017] [Indexed: 01/03/2023]
Abstract
The role of central leptin in regulating the heart from lipid accumulation in lean leptin-sensitive animals has not been fully elucidated. Herein, we investigated the effects of central leptin infusion on the expression of genes involved in cardiac metabolism and its role in the control of myocardial triacylglyceride (TAG) accumulation in adult Wistar rats. Intracerebroventricular (icv) leptin infusion (0.2 µg/day) for 7 days markedly decreased TAG levels in cardiac tissue. Remarkably, the cardiac anti-steatotic effects of central leptin were associated with the selective upregulation of gene and protein expression of peroxisome proliferator-activated receptor β/δ (PPARβ/δ, encoded by Pparb/d) and their target genes, adipose triglyceride lipase (encoded by Pnpla2, herefater referred to as Atgl), hormone sensitive lipase (encoded by Lipe, herefater referred to as Hsl), pyruvate dehydrogenase kinase 4 (Pdk4) and acyl CoA oxidase 1 (Acox1), involved in myocardial intracellular lipolysis and mitochondrial/peroxisomal fatty acid utilization. Besides, central leptin decreased the expression of stearoyl-CoA deaturase 1 (Scd1) and diacylglycerol acyltransferase 1 (Dgat1) involved in TAG synthesis and increased the CPT-1 independent palmitate oxidation, as an index of peroxisomal β-oxidation. Finally, the pharmacological inhibition of PPARβ/δ decreased the effects on gene expression and cardiac TAG content induced by leptin. These results indicate that leptin, acting at central level, regulates selectively the cardiac expression of PPARβ/δ, contributing in this way to regulate the cardiac TAG accumulation in rats, independently of its effects on body weight.
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Affiliation(s)
- Cristina Mora
- BiochemistryFaculty of Science and Technological Chemistry, and Regional Centre for Biomedical Research (CRIB), University of Castilla-La Mancha (UCLM), Ciudad Real, Spain
| | - Cristina Pintado
- BiochemistryFaculty of Environmental Sciences and and CRIB, UCLM, Toledo, Spain
| | - Blanca Rubio
- BiochemistryFaculty of Science and Technological Chemistry, and Regional Centre for Biomedical Research (CRIB), University of Castilla-La Mancha (UCLM), Ciudad Real, Spain
| | - Lorena Mazuecos
- BiochemistryFaculty of Science and Technological Chemistry, and Regional Centre for Biomedical Research (CRIB), University of Castilla-La Mancha (UCLM), Ciudad Real, Spain
| | - Virginia López
- BiochemistryFaculty of Science and Technological Chemistry, and Regional Centre for Biomedical Research (CRIB), University of Castilla-La Mancha (UCLM), Ciudad Real, Spain
| | - Alejandro Fernández
- BiochemistryFaculty of Science and Technological Chemistry, and Regional Centre for Biomedical Research (CRIB), University of Castilla-La Mancha (UCLM), Ciudad Real, Spain
| | - Aurora Salamanca
- BiochemistryFaculty of Science and Technological Chemistry, and Regional Centre for Biomedical Research (CRIB), University of Castilla-La Mancha (UCLM), Ciudad Real, Spain
| | - Brenda Bárcena
- BiochemistryFaculty of Science and Technological Chemistry, and Regional Centre for Biomedical Research (CRIB), University of Castilla-La Mancha (UCLM), Ciudad Real, Spain
| | | | - Carmen Arribas
- BiochemistryFaculty of Environmental Sciences and and CRIB, UCLM, Toledo, Spain
| | - Nilda Gallardo
- BiochemistryFaculty of Science and Technological Chemistry, and Regional Centre for Biomedical Research (CRIB), University of Castilla-La Mancha (UCLM), Ciudad Real, Spain
| | - Antonio Andrés
- BiochemistryFaculty of Science and Technological Chemistry, and Regional Centre for Biomedical Research (CRIB), University of Castilla-La Mancha (UCLM), Ciudad Real, Spain
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Vairamani K, Wang HS, Medvedovic M, Lorenz JN, Shull GE. RNA SEQ Analysis Indicates that the AE3 Cl -/HCO 3- Exchanger Contributes to Active Transport-Mediated CO 2 Disposal in Heart. Sci Rep 2017; 7:7264. [PMID: 28779178 PMCID: PMC5544674 DOI: 10.1038/s41598-017-07585-y] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2017] [Accepted: 06/29/2017] [Indexed: 02/06/2023] Open
Abstract
Loss of the AE3 Cl−/HCO3− exchanger (Slc4a3) in mice causes an impaired cardiac force-frequency response and heart failure under some conditions but the mechanisms are not known. To better understand the functions of AE3, we performed RNA Seq analysis of AE3-null and wild-type mouse hearts and evaluated the data with respect to three hypotheses (CO2 disposal, facilitation of Na+-loading, and recovery from an alkaline load) that have been proposed for its physiological functions. Gene Ontology and PubMatrix analyses of differentially expressed genes revealed a hypoxia response and changes in vasodilation and angiogenesis genes that strongly support the CO2 disposal hypothesis. Differential expression of energy metabolism genes, which indicated increased glucose utilization and decreased fatty acid utilization, were consistent with adaptive responses to perturbations of O2/CO2 balance in AE3-null myocytes. Given that the myocardium is an obligate aerobic tissue and consumes large amounts of O2, the data suggest that loss of AE3, which has the potential to extrude CO2 in the form of HCO3−, impairs O2/CO2 balance in cardiac myocytes. These results support a model in which the AE3 Cl−/HCO3− exchanger, coupled with parallel Cl− and H+-extrusion mechanisms and extracellular carbonic anhydrase, is responsible for active transport-mediated disposal of CO2.
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Affiliation(s)
- Kanimozhi Vairamani
- Department of Molecular Genetics, Biochemistry and Microbiology, University of Cincinnati College of Medicine, Cincinnati, Ohio, 45267, USA
| | - Hong-Sheng Wang
- Department of Pharmacology and Cell Biophysics, University of Cincinnati College of Medicine, Cincinnati, Ohio, 45267, USA
| | - Mario Medvedovic
- Department of Environmental Health, University of Cincinnati College of Medicine, Cincinnati, Ohio, 45267, USA
| | - John N Lorenz
- Department of Cellular and Molecular Physiology, University of Cincinnati College of Medicine, Cincinnati, Ohio, 45267, USA
| | - Gary E Shull
- Department of Molecular Genetics, Biochemistry and Microbiology, University of Cincinnati College of Medicine, Cincinnati, Ohio, 45267, USA.
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Gómez-Hurtado N, Domínguez-Rodríguez A, Mateo P, Fernández-Velasco M, Val-Blasco A, Aizpún R, Sabourin J, Gómez AM, Benitah JP, Delgado C. Beneficial effects of leptin treatment in a setting of cardiac dysfunction induced by transverse aortic constriction in mouse. J Physiol 2017; 595:4227-4243. [PMID: 28374413 DOI: 10.1113/jp274030] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2017] [Accepted: 03/20/2017] [Indexed: 12/11/2022] Open
Abstract
KEY POINTS Leptin, is a 16 kDa pleiotropic peptide not only primarily secreted by adipocytes, but also produced by other tissues, including the heart. Controversy exists regarding the adverse and beneficial effects of leptin on the heart We analysed the effect of a non-hypertensive dose of leptin on cardiac function, [Ca2+ ]i handling and cellular electrophysiology, which participate in the genesis of pump failure and related arrhythmias, both in control mice and in mice subjected to chronic pressure-overload by transverse aorta constriction. We find that leptin activates mechanisms that contribute to cardiac dysfunction under physiological conditions. However, after the establishment of pressure overload, an increase in leptin levels has protective cardiac effects with respect to rescuing the cellular heart failure phenotype. These beneficial effects of leptin involve restoration of action potential duration via normalization of transient outward potassium current and sarcoplasmic reticulum Ca2+ content via rescue of control sarcoplasmic/endoplasmic reticulum Ca2+ ATPase levels and ryanodine receptor function modulation, leading to normalization of Ca2+ handling parameters. ABSTRACT Leptin, is a 16 kDa pleiotropic peptide not only primary secreted by adipocytes, but also produced by other tissues, including the heart. Evidence indicates that leptin may have either adverse or beneficial effects on the heart. To obtain further insights, in the present study, we analysed the effect of leptin treatment on cardiac function, [Ca2+ ]i handling and cellular electrophysiology, which participate in the genesis of pump failure and related arrhythmias, both in control mice and in mice subjected to chronic pressure-overload by transverse aorta constriction (TAC). Three weeks after surgery, animals received either leptin (0.36 mg kg-1 day-1 ) or vehicle via osmotic minipumps for 3 weeks. Echocardiographic measurements showed that, although leptin treatment was deleterious on cardiac function in sham, leptin had a cardioprotective effect following TAC. [Ca2+ ]i transient in cardiomyocytes followed similar pattern. Patch clamp experiments showed prolongation of action potential duration (APD) in TAC and leptin-treated sham animals, whereas, following TAC, leptin reduced the APD towards control values. APD variations were associated with decreased transient outward potassium current and Kv4.2 and KChIP2 protein expression. TAC myocytes showed a higher incidence of triggered activities and spontaneous Ca2+ waves. These proarrhythmic manifestations, related to Ca2+ /calmodulin-dependent protein kinase II and ryanodine receptor phosphorylation, were reduced by leptin. The results of the present study demonstrate that, although leptin treatment was deleterious on cardiac function in control animals, leptin had a cardioprotective effect following TAC, normalizing cardiac function and reducing arrhythmogeneity at the cellular level.
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Affiliation(s)
- Nieves Gómez-Hurtado
- Departament of Pharmacology, School of Medicine, Complutense University, Madrid, Spain.,UMR-S 1180, Inserm, Univ. Paris-Sud, Université Paris-Saclay, Châtenay-Malabry, France.,Division of Clinical Pharmacology, Oates Institute for Experimental Therapeutics, Vanderbilt University School of Medicine, Nashville, TN, USA
| | - Alejandro Domínguez-Rodríguez
- UMR-S 1180, Inserm, Univ. Paris-Sud, Université Paris-Saclay, Châtenay-Malabry, France.,Institute of Biomedicine of Seville/CIBER-CV, Seville, Spain
| | - Philippe Mateo
- UMR-S 1180, Inserm, Univ. Paris-Sud, Université Paris-Saclay, Châtenay-Malabry, France
| | | | | | - Rafael Aizpún
- Departament of Pharmacology, School of Medicine, Complutense University, Madrid, Spain
| | - Jessica Sabourin
- UMR-S 1180, Inserm, Univ. Paris-Sud, Université Paris-Saclay, Châtenay-Malabry, France
| | - Ana María Gómez
- UMR-S 1180, Inserm, Univ. Paris-Sud, Université Paris-Saclay, Châtenay-Malabry, France
| | - Jean-Pierre Benitah
- UMR-S 1180, Inserm, Univ. Paris-Sud, Université Paris-Saclay, Châtenay-Malabry, France
| | - Carmen Delgado
- Departament of Pharmacology, School of Medicine, Complutense University, Madrid, Spain.,Biomedical Research Institute Alberto Sols/CIBER-CV, Madrid, Spain
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25
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A new leptin-mediated mechanism for stimulating fatty acid oxidation: a pivotal role for sarcolemmal FAT/CD36. Biochem J 2016; 474:149-162. [PMID: 27827305 DOI: 10.1042/bcj20160804] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2016] [Revised: 10/03/2016] [Accepted: 11/08/2016] [Indexed: 12/15/2022]
Abstract
Leptin stimulates fatty acid oxidation in muscle and heart; but, the mechanism by which these tissues provide additional intracellular fatty acids for their oxidation remains unknown. We examined, in isolated muscle and cardiac myocytes, whether leptin, via AMP-activated protein kinase (AMPK) activation, stimulated fatty acid translocase (FAT/CD36)-mediated fatty acid uptake to enhance fatty acid oxidation. In both mouse skeletal muscle and rat cardiomyocytes, leptin increased fatty acid oxidation, an effect that was blocked when AMPK phosphorylation was inhibited by adenine 9-β-d-arabinofuranoside or Compound C. In wild-type mice, leptin induced the translocation of FAT/CD36 to the plasma membrane and increased fatty acid uptake into giant sarcolemmal vesicles and into cardiomyocytes. In muscles of FAT/CD36-KO mice, and in cardiomyocytes in which cell surface FAT/CD36 action was blocked by sulfo-N-succinimidyl oleate, the leptin-stimulated influx of fatty acids was inhibited; concomitantly, the normal leptin-stimulated increase in fatty acid oxidation was also prevented, despite the normal leptin-induced increase in AMPK phosphorylation. Conversely, in muscle of AMPK kinase-dead mice, leptin failed to induce the translocation of FAT/CD36, along with a failure to stimulate fatty acid uptake and oxidation. Similarly, when siRNA was used to reduce AMPK in HL-1 cardiomyocytes, leptin failed to induce the translocation of FAT/CD36. Our studies have revealed a novel mechanism of leptin-induced fatty acid oxidation in muscle tissue; namely, this process is dependent on the activation of AMPK to induce the translocation of FAT/CD36 to the plasma membrane, thereby stimulating fatty acid uptake. Without increasing this leptin-stimulated, FAT/CD36-dependent fatty acid uptake process, leptin-stimulated AMPK phosphorylation does not enhance fatty acid oxidation.
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26
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Sawicka M, Janowska J, Chudek J. Potential beneficial effect of some adipokines positively correlated with the adipose tissue content on the cardiovascular system. Int J Cardiol 2016; 222:581-589. [PMID: 27513655 DOI: 10.1016/j.ijcard.2016.07.054] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/17/2016] [Revised: 06/12/2016] [Accepted: 07/04/2016] [Indexed: 01/30/2023]
Abstract
Obesity is a risk factor of cardiovascular diseases. However, in the case of heart failure, obese and overweight patients have a more favourable prognosis compared to patients who have a normal body weight. This phenomenon is referred to as the "obesity paradox," and it is explained by, among others, a positive effect of adipokines produced by adipose tissue, particularly by the tissue located in the direct vicinity of the heart and blood vessels. The favourable effect on the cardiovascular system is mostly associated with adiponectin and omentin, but the levels of these substances are reduced in obese patients. Among the adipokines which levels are positively correlated with the adipose tissue content, favourable activity is demonstrated by apelin, progranulin, chemerin, TNF-α (tumour necrosis factor-)α, CTRP-3 (C1q/tumour necrosis factor (TNF) related protein), leptin, visfatin and vaspin. This activity is associated with the promotion of regeneration processes in the damaged myocardium, formation of new blood vessels, reduction of the afterload, improvement of metabolic processes in cardiomyocytes and myocardial contractile function, inhibition of apoptosis and fibrosis of the myocardium, as well as anti-inflammatory and anti-atheromatous effects. The potential use of these properties in the treatment of heart failure and ischaemic heart disease, as well as in pulmonary hypertension, arterial hypertension and the limitation of the loss of cardiomyocytes during cardioplegia-requiring cardiosurgical procedures, is studied. The most advanced studies focus on analogues of apelin and progranulin.
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Affiliation(s)
- Magdalena Sawicka
- Department of Cardiology, Congenital Heart Diseases and Electrotherapy, Silesian Center for Heart Diseases, 9 Maria Skłodowska- Curie Street, 41-800 Zabrze, Poland; Department of Pathophysiology, Faculty of Medicine, Medical University of Silesia, 18 Medyków Street, 40-027 Katowice, Poland.
| | - Joanna Janowska
- Department of Pathophysiology, Faculty of Medicine, Medical University of Silesia, 18 Medyków Street, 40-027 Katowice, Poland
| | - Jerzy Chudek
- Department of Pathophysiology, Faculty of Medicine, Medical University of Silesia, 18 Medyków Street, 40-027 Katowice, Poland
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Kaulage M, Maji B, Bhat J, Iwasaki Y, Chatterjee S, Bhattacharya S, Muniyappa K. Discovery and Structural Characterization of G-quadruplex DNA in Human Acetyl-CoA Carboxylase Gene Promoters: Its Role in Transcriptional Regulation and as a Therapeutic Target for Human Disease. J Med Chem 2016; 59:5035-50. [PMID: 27058681 DOI: 10.1021/acs.jmedchem.6b00453] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/24/2023]
Abstract
Accumulating evidence suggests that G-quadruplexes play vital roles in gene expression, DNA replication, and recombination. Three distinct promoters (PI, PII, and PIII) regulate human acetyl-CoA carboxylase 1 (ACC1) gene expression. In this study, we asked whether the G-rich sequences within the human ACC1 (PI and PII) promoters can form G-quadruplex structures and regulate normal DNA transactions. Using multiple complementary methods, we show that G-rich sequences of PI and PII promoters form intramolecular G-quadruplex structures and then establish unambiguously the topologies of these structures. Importantly, G-quadruplex formation in ACC1 gene promoter region blocks DNA replication and suppresses transcription, and this effect was further augmented by G-quadruplex stabilizing ligands. Altogether, these results are consistent with the notion that G-quadruplex structures exist within the human ACC1 gene promoter region, whose activity can be suppressed by G-quadruplex stabilizing ligands, thereby revealing a novel regulatory mechanism of ACC1 gene expression and as a possible therapeutic target.
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Affiliation(s)
| | | | - Jyotsna Bhat
- Department of Biophysics, Bose Institute , Kolkata 700054, India
| | - Yasumasa Iwasaki
- Department of Endocrinology, Metabolism, and Nephrology, Kochi Medical School, Kochi University , Nankoku 780-8520, Japan
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28
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Lipid metabolism and signaling in cardiac lipotoxicity. Biochim Biophys Acta Mol Cell Biol Lipids 2016; 1861:1513-24. [PMID: 26924249 DOI: 10.1016/j.bbalip.2016.02.016] [Citation(s) in RCA: 125] [Impact Index Per Article: 13.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2015] [Revised: 02/19/2016] [Accepted: 02/19/2016] [Indexed: 01/01/2023]
Abstract
The heart balances uptake, metabolism and oxidation of fatty acids (FAs) to maintain ATP production, membrane biosynthesis and lipid signaling. Under conditions where FA uptake outpaces FA oxidation and FA sequestration as triacylglycerols in lipid droplets, toxic FA metabolites such as ceramides, diacylglycerols, long-chain acyl-CoAs, and acylcarnitines can accumulate in cardiomyocytes and cause cardiomyopathy. Moreover, studies using mutant mice have shown that dysregulation of enzymes involved in triacylglycerol, phospholipid, and sphingolipid metabolism in the heart can lead to the excess deposition of toxic lipid species that adversely affect cardiomyocyte function. This review summarizes our current understanding of lipid uptake, metabolism and signaling pathways that have been implicated in the development of lipotoxic cardiomyopathy under conditions including obesity, diabetes, aging, and myocardial ischemia-reperfusion. This article is part of a Special Issue entitled: Heart Lipid Metabolism edited by G.D. Lopaschuk.
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29
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Hall ME, Harmancey R, Stec DE. Lean heart: Role of leptin in cardiac hypertrophy and metabolism. World J Cardiol 2015; 7:511-524. [PMID: 26413228 PMCID: PMC4577678 DOI: 10.4330/wjc.v7.i9.511] [Citation(s) in RCA: 69] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/02/2015] [Revised: 06/16/2015] [Accepted: 07/23/2015] [Indexed: 02/06/2023] Open
Abstract
Leptin is an adipokine that has been linked with the cardiovascular complications resulting from obesity such as hypertension and heart disease. Obese patients have high levels of circulating leptin due to increased fat mass. Clinical and population studies have correlated high levels of circulating leptin with the development of cardiac hypertrophy in obesity. Leptin has also been demonstrated to increase the growth of cultured cardiomyocytes. However, several animal studies of obese leptin deficient mice have not supported a role for leptin in promoting cardiac hypertrophy so the role of leptin in this pathological process remains unclear. Leptin is also an important hormone in the regulation of cardiac metabolism where it supports oxidation of glucose and fatty acids. In addition, leptin plays a critical role in protecting the heart from excess lipid accumulation and the formation of toxic lipids in obesity a condition known as cardiac lipotoxicity. This paper focuses on the data supporting and refuting leptin’s role in promoting cardiac hypertrophy as well as its important role in the regulation of cardiac metabolism and protection against cardiac lipotoxicity.
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30
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Munusamy S, do Carmo JM, Hosler JP, Hall JE. Obesity-induced changes in kidney mitochondria and endoplasmic reticulum in the presence or absence of leptin. Am J Physiol Renal Physiol 2015; 309:F731-43. [PMID: 26290368 DOI: 10.1152/ajprenal.00188.2015] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2015] [Accepted: 08/13/2015] [Indexed: 12/17/2022] Open
Abstract
We investigated obesity-induced changes in kidney lipid accumulation, mitochondrial function, and endoplasmic reticulum (ER) stress in the absence of hypertension, and the potential role of leptin in modulating these changes. We compared two normotensive genetic mouse models of obesity, leptin-deficient ob/ob mice and hyperleptinemic melanocortin-4 receptor-deficient mice (LoxTB MC4R-/-), with their respective lean controls. Compared with controls, ob/ob and LoxTB MC4R-/- mice exhibit significant albuminuria, increased creatinine clearance, and high renal triglyceride content. Renal ATP levels were decreased in both obesity models, and mitochondria isolated from both models showed alterations that would lower mitochondrial ATP production. Mitochondria from hyperleptinemic LoxTB MC4R-/- mice kidneys respired NADH-generating substrates (including palmitate) at lower rates due to an apparent decrease in complex I activity, and these mitochondria showed oxidative damage. Kidney mitochondria of leptin-deficient ob/ob mice showed normal rates of respiration with no evidence of oxidative damage, but electron transfer was partially uncoupled from ATP synthesis. A fourfold induction of C/EBP homologous protein (CHOP) expression indicated induction of ER stress in kidneys of hyperleptinemic LoxTB MC4R-/- mice. In contrast, ER stress was not induced in kidneys of leptin-deficient ob/ob mice. Our findings show that obesity, in the absence of hypertension, is associated with renal dysfunction in mice but not with major renal injury. Alterations to mitochondria that lower cellular ATP levels may be involved in obesity-induced renal injury. The type and severity of mitochondrial and ER dysfunction differs depending upon the presence or absence of leptin.
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Affiliation(s)
- Shankar Munusamy
- Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, Mississippi; Mississippi Center for Obesity Research, University of Mississippi Medical Center, Jackson, Mississippi; and College of Pharmacy, Qatar University, Doha, Qatar
| | - Jussara M do Carmo
- Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, Mississippi; Mississippi Center for Obesity Research, University of Mississippi Medical Center, Jackson, Mississippi; and
| | - Jonathan P Hosler
- Department of Biochemistry, University of Mississippi Medical Center, Jackson, Mississippi
| | - John E Hall
- Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, Mississippi; Mississippi Center for Obesity Research, University of Mississippi Medical Center, Jackson, Mississippi; and
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31
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Park KS. Raspberry ketone, a naturally occurring phenolic compound, inhibits adipogenic and lipogenic gene expression in 3T3-L1 adipocytes. PHARMACEUTICAL BIOLOGY 2015; 53:870-875. [PMID: 25429790 DOI: 10.3109/13880209.2014.946059] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/04/2023]
Abstract
CONTEXT Raspberry ketone (RK) is a natural phenolic compound of red raspberry. The dietary intake of RK has been reported to exert anti-obese actions and alter the lipid metabolism in vivo and human studies. OBJECTIVE To elucidate a possible mechanism for anti-obese actions of RK, the effects of RK on the adipogenic and lipogenic gene expression in 3T3-L1 adipocytes were investigated. MATERIALS AND METHODS 3T3-L1 maturing pre-adipocytes were treated from day 2 to day 8 of differentiation and mature adipocytes for 24 h on day 12 with 1, 10, 20, and 50 μM of RK. Triacylglycerols were assessed by spectrophotometry and gene expression by quantitative real-time polymerase chain reaction (qRT-PCR). RESULTS Treatment of adipocytes with RK suppressed adipocyte differentiation and fat accumulation in a concentration-dependent manner. RK suppressed the expression of major genes involved in the adipogenesis pathway including peroxisome proliferator-activated receptor-γ (PPARγ) and CCAAT enhancer binding protein-α (C/EBPα), which led to further down-regulation of adipocyte fatty acid-binding protein-2 (aP2). In addition, treatment with 10 μM of RK also reduced mRNA levels of lipogenic genes such as acetyl-CoA carboxylase-1 (ACC1), fatty acid synthase (FASN), and stearoyl-CoA desaturase-1 (SCD1). In mature adipocytes, RK increased the transcriptional activities of genes involved in lipolysis and the oxidative pathways including adipose triglyceride lipase (ATGL), hormone sensitive lipase (HSL), and carnitine palmitoyl transferase-1B (CPT1B). DISCUSSION AND CONCLUSION These findings suggest that RK holds great promise for an herbal medicine with the biological activities altering the lipid metabolism in 3T3-L1 adipocytes.
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Affiliation(s)
- Kyoung Sik Park
- Department of Biomedical Science, College of Science and Engineering, Cheongju University , Chungbuk , Korea
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32
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Li L, Yoshitomi H, Wei Y, Qin L, Zhou J, Xu T, Wu X, Zhou T, Sun W, Guo X, Wu L, Wang H, Zhang Y, Li C, Liu T, Gao M. Tang-Nai-Kang alleviates pre-diabetes and metabolic disorders and induces a gene expression switch toward fatty acid oxidation in SHR.Cg-Leprcp/NDmcr rats. PLoS One 2015; 10:e0122024. [PMID: 25874615 PMCID: PMC4395456 DOI: 10.1371/journal.pone.0122024] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2014] [Accepted: 02/05/2015] [Indexed: 11/18/2022] Open
Abstract
Increased energy intake and reduced physical activity can lead to obesity, diabetes and metabolic syndrome. Transcriptional modulation of metabolic networks has become a focus of current drug discovery research into the prevention and treatment of metabolic disorders associated with energy surplus and obesity. Tang-Nai-Kang (TNK), a mixture of five herbal plant extracts, has been shown to improve abnormal glucose metabolism in patients with pre-diabetes. Here, we report the metabolic phenotype of SHR.Cg-Leprcp/NDmcr (SHR/cp) rats treated with TNK. Pre-diabetic SHR/cp rats were randomly divided into control, TNK low-dose (1.67 g/kg) and TNK high-dose (3.24 g/kg) groups. After high-dose treatment for 2 weeks, the serum triglycerides and free fatty acids in SHR/cp rats were markedly reduced compared to controls. After 3 weeks of administration, the high dose of TNK significantly reduced the body weight and fat mass of SHR/cp rats without affecting food consumption. Serum fasting glucose and insulin levels in the TNK-treated groups decreased after 6 weeks of treatment. Furthermore, TNK-treated rats exhibited obvious improvements in glucose intolerance and insulin resistance. The improved glucose metabolism may be caused by the substantial reduction in serum lipids and body weight observed in SHR/cp rats starting at 3 weeks of TNK treatment. The mRNA expression of NAD+-dependent deacetylase sirtuin 1 (SIRT1) and genes related to fatty acid oxidation was markedly up-regulated in the muscle, liver and adipose tissue after TNK treatment. Furthermore, TNK promoted the deacetylation of two well-established SIRT1 targets, PPARγ coactivator 1α (PGC1α) and forkhead transcription factor 1 (FOXO1), and induced the phosphorylation of AMP-activated protein kinase (AMPK) and acetyl-CoA carboxylase (ACC) in different tissues. These observations suggested that TNK may be an alternative treatment for pre-diabetes and metabolic syndrome by inducing a gene expression switch toward fat oxidation through the activation of SIRT1 and AMPK signaling.
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Affiliation(s)
- Linyi Li
- Health-cultivation Laboratory of the Ministry of Education, Beijing University of Chinese Medicine, Beijing, China
| | - Hisae Yoshitomi
- School of Pharmaceutical Sciences, Mukogawa Women’s University, Hyogo, Japan
| | - Ying Wei
- Health-cultivation Laboratory of the Ministry of Education, Beijing University of Chinese Medicine, Beijing, China
| | - Lingling Qin
- Health-cultivation Laboratory of the Ministry of Education, Beijing University of Chinese Medicine, Beijing, China
| | - Jingxin Zhou
- Dongzhimen Hospital Eastern Affiliated to Beijing University of Chinese Medicine, Beijing, China
| | - Tunhai Xu
- Health-cultivation Laboratory of the Ministry of Education, Beijing University of Chinese Medicine, Beijing, China
| | - Xinli Wu
- Health-cultivation Laboratory of the Ministry of Education, Beijing University of Chinese Medicine, Beijing, China
| | - Tian Zhou
- Dongfang Hospital Affiliated to Beijing University of Chinese Medicine, Beijing, China
| | - Wen Sun
- Health-cultivation Laboratory of the Ministry of Education, Beijing University of Chinese Medicine, Beijing, China
| | - Xiangyu Guo
- Dongfang Hospital Affiliated to Beijing University of Chinese Medicine, Beijing, China
| | - Lili Wu
- Health-cultivation Laboratory of the Ministry of Education, Beijing University of Chinese Medicine, Beijing, China
| | - Haiyan Wang
- Health-cultivation Laboratory of the Ministry of Education, Beijing University of Chinese Medicine, Beijing, China
| | - Yan Zhang
- Health-cultivation Laboratory of the Ministry of Education, Beijing University of Chinese Medicine, Beijing, China
| | - Chunna Li
- Health-cultivation Laboratory of the Ministry of Education, Beijing University of Chinese Medicine, Beijing, China
| | - Tonghua Liu
- Health-cultivation Laboratory of the Ministry of Education, Beijing University of Chinese Medicine, Beijing, China
- * E-mail: (TL); (MG)
| | - Ming Gao
- School of Pharmaceutical Sciences, Mukogawa Women’s University, Hyogo, Japan
- * E-mail: (TL); (MG)
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20 years of leptin: Role of leptin in cardiomyocyte physiology and physiopathology. Life Sci 2015; 140:10-8. [PMID: 25748420 DOI: 10.1016/j.lfs.2015.02.016] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2015] [Accepted: 02/14/2015] [Indexed: 02/08/2023]
Abstract
Since the discovery of leptin in 1994 by Zhang et al., there have been a number of reports showing its implication in the development of a wide range of cardiovascular diseases. However, there exists some controversy about how leptin can induce or preserve cardiovascular function, as different authors have found contradictory results about leptin beneficial or detrimental effects in leptin deficient/resistant murine models and in wild type tissue and cardiomyocytes. Here, we will focus on the main discoveries about the leptin functions at cardiac level within the last two decades, focusing on its role in cardiac metabolism, remodeling and contractile function.
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Lei MM, Wu SQ, Shao XB, Li XW, Chen Z, Ying SJ, Shi ZD. Creating leptin-like biofunctions by active immunization against chicken leptin receptor in growing chickens. Domest Anim Endocrinol 2015; 50:55-64. [PMID: 25447880 DOI: 10.1016/j.domaniend.2014.09.001] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/29/2014] [Revised: 09/01/2014] [Accepted: 09/04/2014] [Indexed: 12/19/2022]
Abstract
In this study, immunization against chicken leptin receptor (cLEPR) extracellular domain (ECD) was applied to investigate leptin regulation and LEPR biofunction in growing chicken pullets. A recombinant protein (cLEPR ECD) based on the cLEPR complemenary DNA sequence corresponding to the 582nd to 796th amino acid residues of cLEPR mature peptide was prepared and used as antigen. Immunization against cLEPR ECD in growing chickens increased anti-cLEPR ECD antibody titers in blood, enhanced proportions of phosphorylated janus kinase 2 (JAK2) and served as signal transducer and activator of transcription 3 (STAT3) protein in liver tissue. Chicken live weight gain and abdominal fat mass were significantly decreased (P < 0.05), but feed intake was stimulated by cLEPR ECD immunization (P < 0.05). The treatment also upregulated the gene expression levels of lepR, AMP-activated protein kinase (AMPK), acetyl CoA carboxylase-2 (ACC2), and uncoupling protein 3 (UCP3) in liver, abdominal fat, and breast muscle (P < 0.05) but decreased fasn expression levels (P < 0.01). Apart from that of lepR, the expression of appetite-regulating genes, such as orexigenic genes, agouti-related peptide (AgRP) and neuropeptide Y (NPY), were upregulated (P < 0.01), whereas the anorexigenic gene proopiomelanocortin (POMC) was downregulated in the hypothalamic tissue of cLEPR-immunized pullets (P < 0.01). Blood concentrations of metabolic molecules, such as glucose, triglycerides, and very-low-density lipoprotein, were significantly decreased in cLEPR-immunized pullets but those of cholesterol, high-density lipoprotein, and low-density lipoprotein increased. These results demonstrate that antibodies to membrane proximal cLEPR ECD enhance cLEPR signal transduction, which stimulates metabolism and reduces fat deposition in chickens.
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Affiliation(s)
- M M Lei
- Laboratory of Animal Breed Improvement and Reproduction, Institute of Animal Science, Jiangsu Academy of Agricultural Sciences, Nanjing, 210014, China
| | - S Q Wu
- College of Animal Sciences, South China Agricultural University, Guangzhou, 510642, China
| | - X B Shao
- Institute of Guagndong Province Poultry Technology, Guangzhou, 510520, China
| | - X W Li
- College of Animal Sciences, South China Agricultural University, Guangzhou, 510642, China
| | - Z Chen
- Laboratory of Animal Breed Improvement and Reproduction, Institute of Animal Science, Jiangsu Academy of Agricultural Sciences, Nanjing, 210014, China
| | - S J Ying
- Laboratory of Animal Breed Improvement and Reproduction, Institute of Animal Science, Jiangsu Academy of Agricultural Sciences, Nanjing, 210014, China
| | - Z D Shi
- Laboratory of Animal Breed Improvement and Reproduction, Institute of Animal Science, Jiangsu Academy of Agricultural Sciences, Nanjing, 210014, China.
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Dervisevik M, Dinevska-Kovkarovska S, Dimitrovska M, Cipanovska N, Miova B. High dose of aspirin moderates diabetes-induced changes of heart glycogen/glucose metabolism in rats. J Physiol Sci 2014; 64:411-20. [PMID: 25183483 PMCID: PMC10717915 DOI: 10.1007/s12576-014-0335-6] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2014] [Accepted: 08/14/2014] [Indexed: 02/02/2023]
Abstract
Aspirin (ASA), as a multifunctional drug has been used as a hypoglycaemic agent in the treatment of diabetes and severe hyperglycaemia and has been established as a secondary strategy which may prevent many cardiovascular events. In this study we investigated high dose (100 mg/kg b.w./i.p) and time-dependent (2, 7 and 14 days) effects of ASA on the heart key enzymes and substrates from glycogen/glucose metabolism in control and diabetic rats. The results accomplished demonstrated that ASA significantly potentiates glycogen accumulation, as well as decreased blood glucose level and heart glycolytic potential in control rats. The treatment of diabetic rats with ASA caused moderation of the diabetic complication-significant inhibition of glycogen accumulation, lowering of blood glucose, as well as elevation of glycolytic potential. In conclusion, we propose that use of high-dose of ASA has anabolic effects in control rats and reduces heart glycogen glucose complications in diabetic rats. The moderation of diabetes-induced changes is time-dependent and involves reduction of glycogenogenesis and inhibited depression of glycolysis, with a tendency to maintenance control values.
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Affiliation(s)
- M. Dervisevik
- Institute of Biology, Department of Experimental Physiology and Biochemistry, Faculty of Natural Sciences and Mathematics, University “St Cyrilus and Methodius”, Arhimedova 3, 1000 Skopje, Republic of Macedonia
| | - Suzana Dinevska-Kovkarovska
- Institute of Biology, Department of Experimental Physiology and Biochemistry, Faculty of Natural Sciences and Mathematics, University “St Cyrilus and Methodius”, Arhimedova 3, 1000 Skopje, Republic of Macedonia
| | - M. Dimitrovska
- Institute of Biology, Department of Experimental Physiology and Biochemistry, Faculty of Natural Sciences and Mathematics, University “St Cyrilus and Methodius”, Arhimedova 3, 1000 Skopje, Republic of Macedonia
| | - N. Cipanovska
- Institute of Biology, Department of Experimental Physiology and Biochemistry, Faculty of Natural Sciences and Mathematics, University “St Cyrilus and Methodius”, Arhimedova 3, 1000 Skopje, Republic of Macedonia
| | - B. Miova
- Institute of Biology, Department of Experimental Physiology and Biochemistry, Faculty of Natural Sciences and Mathematics, University “St Cyrilus and Methodius”, Arhimedova 3, 1000 Skopje, Republic of Macedonia
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Cortés VA, Cautivo KM, Rong S, Garg A, Horton JD, Agarwal AK. Leptin ameliorates insulin resistance and hepatic steatosis in Agpat2-/- lipodystrophic mice independent of hepatocyte leptin receptors. J Lipid Res 2013; 55:276-88. [PMID: 24293639 DOI: 10.1194/jlr.m045799] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Leptin is essential for energy homeostasis and regulation of food intake. Patients with congenital generalized lipodystrophy (CGL) due to mutations in 1-acylglycerol-3-phosphate-O-acyltransferase 2 (AGPAT2) and the CGL murine model (Agpat2(-/-) mice) both have severe insulin resistance, diabetes mellitus, hepatic steatosis, and low plasma leptin levels. In this study, we show that continuous leptin treatment of Agpat2(-/-) mice for 28 days reduced plasma insulin and glucose levels and normalized hepatic steatosis and hypertriglyceridemia. Leptin also partially, but significantly, reversed the low plasma thyroxine and high corticosterone levels found in Agpat2(-/-) mice. Levels of carbohydrate response element binding protein (ChREBP) were reduced, whereas lipogenic gene expression were increased in the livers of Agpat2(-/-) mice, suggesting that deregulated ChREBP contributed to the development of fatty livers in these mice and that this transcription factor is a target of leptin's beneficial metabolic action. Leptin administration did not change hepatic fatty acid oxidation enzymes mRNA levels in Agpat2(-/-) mice. The selective deletion of leptin receptors only in hepatocytes did not prevent the positive metabolic actions of leptin in Agpat2(-/-) mice, supporting the notion that the majority of metabolic actions of leptin are dependent on its action in nonhepatocyte cells and/or the central nervous system.
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Affiliation(s)
- Víctor A Cortés
- Department of Molecular Genetics, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX
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Kostovski E, Boon H, Hjeltnes N, Lundell LS, Ahlsén M, Chibalin AV, Krook A, Iversen PO, Widegren U. Altered content of AMP-activated protein kinase isoforms in skeletal muscle from spinal cord injured subjects. Am J Physiol Endocrinol Metab 2013; 305:E1071-80. [PMID: 24022865 DOI: 10.1152/ajpendo.00132.2013] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
AMP-activated protein kinase (AMPK) is a pivotal regulator of energy homeostasis. Although downstream targets of AMPK are widely characterized, the physiological factors governing isoform expression of this protein kinase are largely unknown. Nerve/contractile activity has a major impact on the metabolic phenotype of skeletal muscle, therefore likely to influence AMPK isoform expression. Spinal cord injury represents an extreme form of physical inactivity, with concomitant changes in skeletal muscle metabolism. We assessed the influence of longstanding and recent spinal cord injury on protein abundance of AMPK isoforms in human skeletal muscle. We also determined muscle fiber type as a marker of glycolytic or oxidative metabolism. In subjects with longstanding complete injury, protein abundance of the AMPKγ3 subunit, as well as myosin heavy chain (MHC) IIa and IIx, were increased, whereas abundance of the AMPKγ1 subunit and MHC I were decreased. Similarly, abundance of AMPKγ3 and MHC IIa proteins were increased, whereas AMPKα2, -β1, and -γ1 subunits and MHC I abundance was decreased during the first year following injury, reflecting a more glycolytic phenotype of the skeletal muscle. However, in incomplete cervical lesions, partial recovery of muscle function attenuated the changes in the isoform profile of AMPK and MHC. Furthermore, exercise training (electrically stimulated leg cycling) partly normalized mRNA expression of AMPK isoforms. Thus, physical activity affects the relative expression of AMPK isoforms. In conclusion, skeletal muscle abundance of AMPK isoforms is related to physical activity and/or muscle fiber type. Thus, physical/neuromuscular activity is an important determinant of isoform abundance of AMPK and MCH. This further underscores the need for physical activity as part of a treatment regimen after spinal cord injury to maintain skeletal muscle metabolism.
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Affiliation(s)
- Emil Kostovski
- Section for Spinal Cord Injury, Sunnaas Rehabilitation Hospital, Nesoddtangen, Norway
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Neuroendocrine and cardiac metabolic dysfunction and NLRP3 inflammasome activation in adipose tissue and pancreas following chronic spinal cord injury in the mouse. ASN Neuro 2013; 5:243-55. [PMID: 23924318 PMCID: PMC3789215 DOI: 10.1042/an20130021] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
Abstract
CVD (cardiovascular disease) represents a leading cause of mortality in chronic SCI (spinal cord injury). Several component risk factors are observed in SCI; however, the underlying mechanisms that contribute to these risks have not been defined. Central and peripheral chronic inflammation is associated with metabolic dysfunction and CVD, including adipokine regulation of neuroendocrine and cardiac function and inflammatory processes initiated by the innate immune response. We use female C57 Bl/6 mice to examine neuroendocrine, cardiac, adipose and pancreatic signaling related to inflammation and metabolic dysfunction in response to experimentally induced chronic SCI. Using immuno-histochemical, -precipitation, and -blotting analysis, we show decreased POMC (proopiomelanocortin) and increased NPY (neuropeptide-Y) expression in the hypothalamic ARC (arcuate nucleus) and PVN (paraventricular nucleus), 1-month post-SCI. Long-form leptin receptor (Ob-Rb), JAK2 (Janus kinase)/STAT3 (signal transducer and activator of transcription 3)/p38 and RhoA/ROCK (Rho-associated kinase) signaling is significantly increased in the heart tissue post-SCI, and we observe the formation and activation of the NLRP3 (NOD-like receptor family, pyrin domain containing 3) inflammasome in VAT (visceral adipose tissue) and pancreas post-SCI. These data demonstrate neuroendocrine signaling peptide alterations, associated with central inflammation and metabolic dysfunction post-SCI, and provide evidence for the peripheral activation of signaling mechanisms involved in cardiac, VAT and pancreatic inflammation and metabolic dysfunction post-SCI. Further understanding of biological mechanisms contributing to SCI-related inflammatory processes and metabolic dysfunction associated with CVD pathology may help to direct therapeutic and rehabilitation countermeasures.
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Roles of Fatty Acid oversupply and impaired oxidation in lipid accumulation in tissues of obese rats. J Lipids 2013; 2013:420754. [PMID: 23762564 PMCID: PMC3666279 DOI: 10.1155/2013/420754] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2013] [Accepted: 04/19/2013] [Indexed: 12/30/2022] Open
Abstract
To test the roles of lipid oversupply versus oxidation in causing tissue lipid accumulation associated with insulin resistance/obesity, we studied in vivo fatty acid (FA) metabolism in obese (Obese) and lean (Lean) Zucker rats. Indices of local FA utilization and storage were calculated using the partially metabolizable [9,10-3H]-(R)-2-bromopalmitate (3H-R-BrP) and [U-14C]-palmitate (14C-P) FA tracers, respectively. Whole-body FA appearance (Ra) was estimated from plasma 14C-P kinetics. Whole-body FA oxidation rate (Rox) was assessed using 3H2O production from 3H-palmitate infusion, and tissue FA oxidative capacity was evaluated ex vivo. In the basal fasting state Obese had markedly elevated FA levels and Ra, associated with elevated FA utilization and storage in most tissues. Estimated rates of muscle FA oxidation were not lower in obese rats and were similarly enhanced by contraction in both lean and obese groups. At comparable levels of FA availability, achieved by nicotinic acid, Rox was lower in Obese than Lean. In Obese rats, FA oxidative capacity was 35% higher than that in Lean in skeletal muscle, 67% lower in brown fat and comparable in other organs. In conclusion, lipid accumulation in non-adipose tissues of obese Zucker rats appears to result largely from systemic FA oversupply.
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Zu X, Zhong J, Luo D, Tan J, Zhang Q, Wu Y, Liu J, Cao R, Wen G, Cao D. Chemical genetics of acetyl-CoA carboxylases. Molecules 2013; 18:1704-19. [PMID: 23358327 PMCID: PMC6269866 DOI: 10.3390/molecules18021704] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2012] [Revised: 01/03/2013] [Accepted: 01/11/2013] [Indexed: 12/16/2022] Open
Abstract
Chemical genetic studies on acetyl-CoA carboxylases (ACCs), rate-limiting enzymes in long chain fatty acid biosynthesis, have greatly advanced the understanding of their biochemistry and molecular biology and promoted the use of ACCs as targets for herbicides in agriculture and for development of drugs for diabetes, obesity and cancers. In mammals, ACCs have both biotin carboxylase (BC) and carboxyltransferase (CT) activity, catalyzing carboxylation of acetyl-CoA to malonyl-CoA. Several classes of small chemicals modulate ACC activity, including cellular metabolites, natural compounds, and chemically synthesized products. This article reviews chemical genetic studies of ACCs and the use of ACCs for targeted therapy of cancers.
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Affiliation(s)
- Xuyu Zu
- Institute of Clinical Medicine, the First Affiliated Hospital, University of South China, Hengyang 421001, Hunan, China
| | - Jing Zhong
- Institute of Clinical Medicine, the First Affiliated Hospital, University of South China, Hengyang 421001, Hunan, China
| | - Dixian Luo
- Institute of Translational Medicine & Department of Laboratory Medicine, the First People’s Hospital of Chenzhou, 102 Luojiajing Road, Chenzhou 423000, Hunan, China
| | - Jingjing Tan
- Institute of Clinical Medicine, the First Affiliated Hospital, University of South China, Hengyang 421001, Hunan, China
| | - Qinghai Zhang
- Institute of Clinical Medicine, the First Affiliated Hospital, University of South China, Hengyang 421001, Hunan, China
| | - Ying Wu
- Institute of Clinical Medicine, the First Affiliated Hospital, University of South China, Hengyang 421001, Hunan, China
| | - Jianghua Liu
- Institute of Clinical Medicine, the First Affiliated Hospital, University of South China, Hengyang 421001, Hunan, China
| | - Renxian Cao
- Institute of Clinical Medicine, the First Affiliated Hospital, University of South China, Hengyang 421001, Hunan, China
- Authors to whom correspondence should be addressed; E-Mails: (R.C.); (D.C.); Tel.: +86-217-545-9703 (D.C.); Fax: +86-217-545-9718 (D.C.)
| | - Gebo Wen
- Institute of Clinical Medicine, the First Affiliated Hospital, University of South China, Hengyang 421001, Hunan, China
| | - Deliang Cao
- Department of Microbiology, Immunology and Cell Biology, Simmons Cancer Institute, Southern Illinois University School of Medicine, 913 N. Rutledge Street, Springfield, IL 62794, USA
- Authors to whom correspondence should be addressed; E-Mails: (R.C.); (D.C.); Tel.: +86-217-545-9703 (D.C.); Fax: +86-217-545-9718 (D.C.)
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Hall ME, Smith G, Hall JE, Stec DE. Cardiomyocyte-specific deletion of leptin receptors causes lethal heart failure in Cre-recombinase-mediated cardiotoxicity. Am J Physiol Regul Integr Comp Physiol 2012; 303:R1241-50. [PMID: 23115124 DOI: 10.1152/ajpregu.00292.2012] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
Although disruption of leptin signaling is associated with obesity as well as cardiac lipid accumulation and dysfunction, it has been difficult to separate the direct effects of leptin on the heart from those associated with the effects of leptin on body weight and fat mass. Using Cre-loxP recombinase technology, we developed tamoxifen-inducible, cardiomyocyte-specific leptin receptor-deficient mice to assess the role of leptin in regulating cardiac function. Cre recombinase activation in the heart resulted in transient reduction in left ventricular systolic function which recovered to normal levels by day 10. However, when cardiomyocyte leptin receptors were deleted in the setting of Cre recombinase-induced left ventricular dysfunction, irreversible lethal heart failure was observed in less than 10 days in all mice. Heart failure after leptin receptor deletion was associated with marked decreases of cardiac mitochondrial ATP, phosphorylated mammalian target of rapamycin (mTOR), and AMP-activated kinase (pAMPK). Our results demonstrate that specific deletion of cardiomyocyte leptin receptors, in the presence of increased Cre recombinase expression, causes lethal heart failure associated with decreased cardiac energy production. These observations indicate that leptin plays an important role in regulating cardiac function in the setting of cardiac stress caused by Cre-recombinase expression, likely through actions on cardiomyocyte energy metabolism.
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Affiliation(s)
- Michael E Hall
- Department of Physiology and Biophysics, Center for Excellence in Cardiovascular-Renal Research, University of Mississippi Medical Center, Jackson, MS 39216, USA
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Abstract
1. Leptin is a 16-kDa hormone, synthesized primarily by adipocyte, which acts as a key factor for maintenance of energy homeostasis in central and peripheral tissues. In most obese individuals, serum leptin levels are increased and correlate with the individual's body mass index. 2. Abundant investigations ranging from clinical and animal model studies to in vitro analyses show that leptin plays a pivotal role in obesity-related cardiovascular diseases (CVD). Hyperleptinaemia has been confirmed to be a predictor of acute cardiovascular events. However, some studies have shown that leptin has a cardioprotective effect in leptin-deficient models. These data suggest the influences of leptin on the pathophysiology of cardiovascular diseases are complex and not completely understood. 3. In the present review, we summarize the major leptin signalling pathways, including Janus-activated kinase/signal transducers and activators of transcription (Jak/STAT), mitogen-activated protein kinases (MAPK), and phosphatidylinositol 3-kinase (PI-3K) signalling pathways, and analyse the probable mechanisms of selective leptin resistance. We then provide a detailed review of the effects of leptin on the cardiovascular system, including sympathoactivation, oxidative stress, vascular inflammation, endothelial dysfunction, vascular cell proliferation, cardiomyocytes hypertrophy, as well as fatty acid metabolism, all of which contribute to the pathogenesis of cardiovascular diseases (e.g. ischaemic heart disease). The central premise of this review is to elucidate the mechanisms by which leptin affects the cardiovascular function and provide insight into obesity-related CVD.
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Affiliation(s)
- Ning Hou
- Department of Pharmacology, Guangzhou institute of Cardiovascular Disease, Guangzhou key laboratory of Cardiovascular Disease, and Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, China
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Alterations in mouse hypothalamic adipokine gene expression and leptin signaling following chronic spinal cord injury and with advanced age. PLoS One 2012; 7:e41073. [PMID: 22815920 PMCID: PMC3397960 DOI: 10.1371/journal.pone.0041073] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2012] [Accepted: 06/18/2012] [Indexed: 01/19/2023] Open
Abstract
Chronic spinal cord injury (SCI) results in an accelerated trajectory of several cardiovascular disease (CVD) risk factors and related aging characteristics, however the molecular mechanisms that are activated have not been explored. Adipokines and leptin signaling are known to play a critical role in neuro-endocrine regulation of energy metabolism, and are now implicated in central inflammatory processes associated with CVD. Here, we examine hypothalamic adipokine gene expression and leptin signaling in response to chronic spinal cord injury and with advanced age. We demonstrate significant changes in fasting-induced adipose factor (FIAF), resistin (Rstn), long-form leptin receptor (LepRb) and suppressor of cytokine-3 (SOCS3) gene expression following chronic SCI and with advanced age. LepRb and Jak2/stat3 signaling is significantly decreased and the leptin signaling inhibitor SOCS3 is significantly elevated with chronic SCI and advanced age. In addition, we investigate endoplasmic reticulum (ER) stress and activation of the uncoupled protein response (UPR) as a biological hallmark of leptin resistance. We observe the activation of the ER stress/UPR proteins IRE1, PERK, and eIF2alpha, demonstrating leptin resistance in chronic SCI and with advanced age. These findings provide evidence for adipokine-mediated inflammatory responses and leptin resistance as contributing to neuro-endocrine dysfunction and CVD risk following SCI and with advanced age. Understanding the underlying mechanisms contributing to SCI and age related CVD may provide insight that will help direct specific therapeutic interventions.
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Changes in cardiac energy metabolic pathways in overweighed rats fed a high-fat diet. Eur J Nutr 2012; 52:847-56. [PMID: 22695689 DOI: 10.1007/s00394-012-0392-7] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2011] [Accepted: 05/25/2012] [Indexed: 12/23/2022]
Abstract
BACKGROUND Heart produces ATP through long-chain fatty acids beta oxidation. PURPOSE To analyze whether in ventricular myocardium, high-fat diet may modify the expression of proteins associated with energy metabolism before myocardial function was affected. METHODS Wistar Kyoto rats were divided into two groups: (a) rats fed standard diet (control; n = 6) and (b) rats fed high-fat diet (HFD; n = 6). Proteins from left ventricles were analyzed by two-dimensional electrophoresis, mass spectrometry and Western blotting. RESULTS Rats fed with HFD showed higher body weight, insulin, glucose, leptin and total cholesterol plasma levels as compared with those fed with standard diet. However, myocardial functional parameters were not different between them. The protein expression of 3-ketoacyl-CoA thiolase, acyl-CoA hydrolase mitochondrial precursor and enoyl-CoA hydratase, three long-chain fatty acid β-oxidation-related enzymes, and carnitine-O-palmitoyltransferase I was significantly higher in left ventricles from HFD rats. Protein expression of triosephosphate isomerase was higher in left ventricles from HFD rats than in those from control. Two α/β-enolase isotypes and glyceraldehyde-3-phosphate isomerase were significantly increased in HFD rats as compared with control. Pyruvate and lactate contents were similar in HFD and control groups. Expression of proteins associated with Krebs cycle and mitochondrial oxidative phosphorylation was higher in HFD rats. CONCLUSIONS Expression of proteins involved in left ventricle metabolic energy was enhanced before myocardial functionality was affected in rats fed with HFD. These findings may probably indicate higher cardiac energy requirement due to weight increase by HFD.
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Schaab M, Kausch H, Klammt J, Nowicki M, Anderegg U, Gebhardt R, Rose-John S, Scheller J, Thiery J, Kratzsch J. Novel regulatory mechanisms for generation of the soluble leptin receptor: implications for leptin action. PLoS One 2012; 7:e34787. [PMID: 22545089 PMCID: PMC3335825 DOI: 10.1371/journal.pone.0034787] [Citation(s) in RCA: 48] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2011] [Accepted: 03/08/2012] [Indexed: 12/19/2022] Open
Abstract
BACKGROUND The adipokine leptin realizes signal transduction via four different membrane-anchored leptin receptor (Ob-R) isoforms in humans. However, the amount of functionally active Ob-R is affected by constitutive shedding of the extracellular domain via a so far unknown mechanism. The product of the cleavage process the so-called soluble leptin receptor (sOb-R) is the main binding protein for leptin in human blood and modulates its bioavailability. sOb-R levels are differentially regulated in metabolic disorders like type 1 diabetes mellitus or obesity and can, therefore, enhance or reduce leptin sensitivity. METHODOLOGY/PRINCIPAL FINDINGS To describe mechanisms of Ob-R cleavage and to investigate the functional significance of differential sOb-R levels we established a model of HEK293 cells transiently transfected with different human Ob-R isoforms. Using siRNA knockdown experiments we identified ADAM10 (A Disintegrin And Metalloproteinase 10) as a major protease for constitutive and activated Ob-R cleavage. Additionally, the induction of lipotoxicity and apoptosis led to enhanced shedding shown by increased levels of the soluble leptin receptor (sOb-R) in cell supernatants. Conversely, high leptin concentrations and ER stress reduced sOb-R levels. Decreased amounts of sOb-R due to ER stress were accompanied by impaired leptin signaling and reduced leptin binding. CONCLUSIONS Lipotoxicity and apoptosis increased Ob-R cleavage via ADAM10-dependent mechanisms. In contrast high leptin levels and ER stress led to reduced sOb-R levels. While increased sOb-R concentrations seem to directly block leptin action, reduced amounts of sOb-R may reflect decreased membrane expression of Ob-R. These findings could explain changes of leptin sensitivity which are associated with variations of serum sOb-R levels in metabolic diseases.
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Affiliation(s)
- Michael Schaab
- Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University of Leipzig, Leipzig, Germany
| | - Henriette Kausch
- Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University of Leipzig, Leipzig, Germany
| | - Juergen Klammt
- Hospital for Children and Adolescents, University of Leipzig, Leipzig, Germany
| | - Marcin Nowicki
- Institute of Anatomy, Faculty of Medicine, University of Leipzig, Leipzig, Germany
| | - Ulf Anderegg
- Department of Dermatology, Venerology and Allergology, Faculty of Medicine, University of Leipzig, Leipzig, Germany
| | - Rolf Gebhardt
- Institute of Biochemistry, Faculty of Medicine, University of Leipzig, Leipzig, Germany
| | - Stefan Rose-John
- Institute of Biochemistry, Christian-Albrechts-University Kiel, Kiel, Germany
| | - Juergen Scheller
- Institute of Biochemistry, Christian-Albrechts-University Kiel, Kiel, Germany
| | - Joachim Thiery
- Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University of Leipzig, Leipzig, Germany
| | - Juergen Kratzsch
- Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University of Leipzig, Leipzig, Germany
- * E-mail:
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Lee JW, Choe SS, Jang H, Kim J, Jeong HW, Jo H, Jeong KH, Tadi S, Park MG, Kwak TH, Man Kim J, Hyun DH, Kim JB. AMPK activation with glabridin ameliorates adiposity and lipid dysregulation in obesity. J Lipid Res 2012; 53:1277-86. [PMID: 22493094 DOI: 10.1194/jlr.m022897] [Citation(s) in RCA: 78] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
In this study, we demonstrate that activation of AMP-activated protein kinase (AMPK) with glabridin alleviates adiposity and hyperlipidemia in obesity. In several obese rodent models, glabridin decreased body weight and adiposity with a concomitant reduction in fat cell size. Further, glabridin ameliorated fatty liver and plasma levels of triglyceride and cholesterol. In accordance with these findings, glabridin suppressed the expression of lipogenic genes such as sterol regulatory element binding transcription factor (SREBP)-1c, fatty acid synthase (FAS), acetyl-CoA carboxylase (ACC), and stearoyl-CoA desaturase (SCD)-1 in white adipose tissues and liver, whereas it elevated the expression of fatty acid oxidation genes such as carnitine palmitoyl transferase (CPT)1, acyl-CoA oxidase (ACO), and peroxisome proliferator-activated receptor (PPAR)α in muscle. Moreover, glabridin enhanced phosphorylation of AMPK in muscle and liver and promoted fatty acid oxidation by modulating mitochondrial activity. Together, these data suggest that glabridin is a novel AMPK activator that would exert therapeutic effects in obesity-related metabolic disorders.
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Affiliation(s)
- Joo-Won Lee
- Department of Biophysics and Chemical Biology, School of Biological Sciences, Institute of Molecular Biology & Genetics, Seoul National University, Seoul 151-742, Korea
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Abel ED, Sweeney G. Modulation of the cardiovascular system by leptin. Biochimie 2012; 94:2097-103. [PMID: 22490727 DOI: 10.1016/j.biochi.2012.03.019] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2012] [Accepted: 03/26/2012] [Indexed: 01/20/2023]
Abstract
It is well established that individuals with the metabolic syndrome have a significantly increased risk of cardiovascular disease and much effort has been expended to elicit the underlying mechanisms. Various studies have proposed that excessive or deficient physiological effects mediated by leptin make an important contribution, yet many paradoxical observations often preclude a clear definition of the role of leptin. This review article will briefly discuss principal and most recent evidence on direct and indirect regulation of the cardiovascular system by leptin, focusing on cardiac structural and functional as well as vascular effects.
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Affiliation(s)
- E Dale Abel
- Division of Endocrinology, Metabolism and Diabetes and Program in Molecular Medicine, University of Utah School of Medicine, Salt Lake City, Utah, USA
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Wolsk E, Mygind H, Grøndahl TS, Pedersen BK, van Hall G. The role of leptin in human lipid and glucose metabolism: the effects of acute recombinant human leptin infusion in young healthy males. Am J Clin Nutr 2011; 94:1533-44. [PMID: 22071709 DOI: 10.3945/ajcn.111.012260] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
Abstract
BACKGROUND Obese and lean humans treated with leptin have not experienced convincing weight-loss results compared with the dramatic weight losses observed in obese rodents. OBJECTIVE We sought to investigate the effect of acutely elevating leptin to concentrations observed in obese individuals on muscle and adipose tissue metabolism and muscle signaling in healthy lean males. DESIGN Healthy, lean, postabsorptive males were infused with either recombinant human leptin (rhleptin; n = 8) or saline (control; n = 8) for 4 h, which elicited leptin concentrations of ~ 20 and ~ 1 ng/mL, respectively. Systemic, skeletal muscle, and adipose tissue fat and glucose metabolism in vivo were assessed before, during, and 2 h after cessation of the infusion. Skeletal muscle biopsy specimens were obtained to quantify changes in signal transducers and activators of transcription-5'AMP-activated protein kinase (STAT-AMPK) signaling. RESULTS During the infusion of rhleptin, no differences in either systemic, skeletal muscle, or adipose tissue glucose or fat metabolism were observed. These observations were made despite increased activation of STAT (~ 17-fold) and AMPK (1.43-fold) after 1 h of rhleptin infusion. After the rhleptin infusion, an increase in systemic palmitate and fat oxidation was observed (P < 0.0003), which likely was caused by a concomitant increase in skeletal muscle palmitate oxidation (P < 0.02). This was observed despite lowered leptin concentrations and basal skeletal muscle STAT-AMPK signaling. CONCLUSIONS Elevating circulating leptin concentrations to concentrations comparable with those of obese individuals increases human in vivo skeletal muscle signaling through the AMPK pathway and causes an increase in skeletal muscle fatty acid oxidation. Abdominal adipose tissue was unaffected by the acute physiologic increase in leptin concentrations.
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Affiliation(s)
- Emil Wolsk
- Centre of Inflammation and Metabolism, Department of Infectious Diseases, Rigshospitalet, Faculty of Health Sciences, University of Copenhagen, Denmark.
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Zajac DM, Cerasale DJ, Landman S, Guglielmo CG. Behavioral and physiological effects of photoperiod-induced migratory state and leptin on Zonotrichia albicollis: II. Effects on fatty acid metabolism. Gen Comp Endocrinol 2011; 174:269-75. [PMID: 21925178 DOI: 10.1016/j.ygcen.2011.08.024] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/19/2010] [Revised: 08/26/2011] [Accepted: 08/30/2011] [Indexed: 10/17/2022]
Abstract
The migratory flights of birds are fuelled largely by fatty acids. Fatty acid transporters, including FAT/CD36, FABPpm and H-FABP, and enzymes involved in fatty acid oxidation (CPT, CS, HOAD) are seasonally up-regulated in flight muscle to meet the demands of this intense aerobic exercise. The mechanisms that control these biochemical changes in response to migration are mostly unknown. We studied the effects of a photoperiod-induced migratory state and a 7 day treatment with murine leptin (1 μg/g body mass, twice per day) on fatty acid metabolism in captive white-throated sparrows. Sparrows that were exposed to a long-day migratory photoperiod increased flight muscle FAT/CD36 and H-FABP mRNA by 154% and 589%, respectively, and had 32% higher H-FABP protein than birds kept on a short-day photoperiod that mimicked wintering conditions. Migrants increased activities of flight muscle CPT, CS and HOAD by 57%, 23% and 74%, respectively, and decreased LDH activity by 31%, reflecting an increase in aerobic relative to anaerobic capacity. The expression of fatty acid transporters and the activities of metabolic enzymes in cardiac muscle were unaffected by migratory state. Leptin had no effect on transport proteins or enzymes in either skeletal or cardiac muscle suggesting that other signaling pathways control fatty acid metabolism during migration. These data indicate that photoperiod alone is sufficient to prime flight muscles for migratory flights by promoting enhanced protein-mediated fatty acid transport and oxidation. However, the endocrine controls and other factors underlying these changes remain to be thoroughly investigated.
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Affiliation(s)
- Daria M Zajac
- Department of Biology, Advanced Facility for Avian Research, University of Western Ontario, London, ON, Canada N6A 5B7
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Kim MS, Wang Y, Rodrigues B. Lipoprotein lipase mediated fatty acid delivery and its impact in diabetic cardiomyopathy. Biochim Biophys Acta Mol Cell Biol Lipids 2011; 1821:800-8. [PMID: 22024251 DOI: 10.1016/j.bbalip.2011.10.001] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2011] [Revised: 09/15/2011] [Accepted: 10/03/2011] [Indexed: 01/29/2023]
Abstract
Although cardiovascular disease is the leading cause of diabetes-related death, its etiology is still not understood. The immediate change that occurs in the diabetic heart is altered energy metabolism where in the presence of impaired glucose uptake, glycolysis, and pyruvate oxidation, the heart switches to exclusively using fatty acids (FA) for energy supply. It does this by rapidly amplifying its lipoprotein lipase (LPL-a key enzyme, which hydrolyzes circulating lipoprotein-triglyceride to release FA) activity at the coronary lumen. An abnormally high capillary LPL could provide excess fats to the heart, leading to a number of metabolic, morphological, and mechanical changes, and eventually to cardiac disease. Unlike the initial response, chronic severe diabetes "turns off" LPL, this is also detrimental to cardiac function. In this review, we describe a number of post-translational mechanisms that influence LPL vesicle formation, actin cytoskeleton rearrangement, and transfer of LPL from cardiomyocytes to the vascular lumen to hydrolyze lipoprotein-triglyceride following diabetes. Appreciating the mechanism of how the heart regulates its LPL following diabetes should allow the identification of novel targets for therapeutic intervention, to prevent heart failure. This article is part of a Special Issue entitled Triglyceride Metabolism and Disease.
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Affiliation(s)
- Min Suk Kim
- Molecular and Cellular Pharmacology, Faculty of Pharmaceutical Sciences, The University of British Columbia, Vancouver, BC, Canada V6T 1Z3
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