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Bake S, Pinson MR, Pandey S, Chambers JP, Mota R, Fairchild AE, Miranda RC, Sohrabji F. Prenatal alcohol-induced sex differences in immune, metabolic and neurobehavioral outcomes in adult rats. Brain Behav Immun 2021; 98:86-100. [PMID: 34390803 PMCID: PMC8591773 DOI: 10.1016/j.bbi.2021.08.207] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/29/2020] [Revised: 07/10/2021] [Accepted: 08/06/2021] [Indexed: 12/15/2022] Open
Abstract
Prenatal alcohol exposure (PAE) can result in neurobehavioral anomalies, that may be exacerbated by co-occurring metabolic and immune system deficits. To test the hypothesis that the peripheral inflammation in adult PAE offspring is linked to poor glucose metabolism and neurocognitive deficits, pregnant Sprague-Dawley rats were exposed to ethanol vapor or ambient air during the latter half of gestation. We assessed, in adult offspring of both sexes, performance on a battery of neurocognitive behaviors, glucose tolerance, circulating and splenic immune cells by flow-cytometry, and circulating and tissue (liver, mesenteric adipose, and spleen) cytokines by multiplexed assays. PAE reduced both the ratio of spleen to body weight and splenic regulatory T-cell (Treg) numbers. PAE males, but not females exhibited an increase in circulating monocytes. Overall, PAE males exhibited a suppression of cytokine levels, while PAE females exhibited elevated cytokines in mesenteric adipose tissue (IL-6 and IL1α) and liver (IFN-γ, IL-1β, IL-13, IL-18, IL-12p70, and MCP-1), along with increased glucose intolerance. Behavioral analysis also showed sex-dependent PAE effects. PAE-males exhibited increased anxiety-like behavior while PAE-females showed decreased social interaction. PAE offspring of both sexes exhibited impaired recognition of novel objects. Multilinear regression modeling to predict the association between peripheral immune status, glucose intolerance and behavioral outcomes, showed that in PAE offspring, higher levels of adipose leptin and liver TNF- α predicted higher circulating glucose levels. Lower liver IL-1 α and higher plasma fractalkine predicted more time spent in the center of an open-field with sex being an additional predictor. Higher circulating and splenic Tregs predicted better social interaction in the PAE-offspring. Collectively, our data show that peripheral immune status is a persistent, sex-dependent predictor of glucose intolerance and neurobehavioral function in adult PAE offspring.
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Affiliation(s)
- Shameena Bake
- Women's Health in Neuroscience Program, and Department of Neuroscience and Experimental Therapeutics, College of Medicine, Texas A&M University, Bryan, TX 77807, USA
| | - Marisa R Pinson
- Women's Health in Neuroscience Program, and Department of Neuroscience and Experimental Therapeutics, College of Medicine, Texas A&M University, Bryan, TX 77807, USA
| | - Sivani Pandey
- Women's Health in Neuroscience Program, and Department of Neuroscience and Experimental Therapeutics, College of Medicine, Texas A&M University, Bryan, TX 77807, USA
| | - Joanna P Chambers
- Women's Health in Neuroscience Program, and Department of Neuroscience and Experimental Therapeutics, College of Medicine, Texas A&M University, Bryan, TX 77807, USA
| | - Roxanna Mota
- Women's Health in Neuroscience Program, and Department of Neuroscience and Experimental Therapeutics, College of Medicine, Texas A&M University, Bryan, TX 77807, USA
| | - Ashlyn E Fairchild
- Women's Health in Neuroscience Program, and Department of Neuroscience and Experimental Therapeutics, College of Medicine, Texas A&M University, Bryan, TX 77807, USA
| | - Rajesh C Miranda
- Women's Health in Neuroscience Program, and Department of Neuroscience and Experimental Therapeutics, College of Medicine, Texas A&M University, Bryan, TX 77807, USA.
| | - Farida Sohrabji
- Women's Health in Neuroscience Program, and Department of Neuroscience and Experimental Therapeutics, College of Medicine, Texas A&M University, Bryan, TX 77807, USA.
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Liu D, Zhang T, Wang Y, Xia L. The Centrality of Obesity in the Course of Severe COVID-19. Front Endocrinol (Lausanne) 2021; 12:620566. [PMID: 33776917 PMCID: PMC7992974 DOI: 10.3389/fendo.2021.620566] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/23/2020] [Accepted: 02/11/2021] [Indexed: 12/15/2022] Open
Abstract
The ongoing coronavirus disease 2019 (COVID-19) pandemic caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has become a global public health challenge. Most patients do not experience severe complications, but approximately 25% of patients progress to acute respiratory distress syndrome (ARDS), and the mortality rate is approximately 5-7%. Clinical findings have determined several risk factors for severe complications and mortality in COVID-19 patients, such as advanced age, smoking, obesity, and chronic diseases. Obesity is a common and serious health problem worldwide that initiates a cascade of disorders, including hypertension, cardiovascular disease (CVD), diabetes mellitus, and chronic kidney disease (CKD). The presence of these disorders is linked to a more severe course of COVID-19. Given the "epidemic" of obesity worldwide and the importance of obesity in the progression of COVID-19, we investigated the mechanisms through which obesity increases the susceptibility to and severity of COVID-19 to support the selection of more appropriate therapies for individuals with obesity.
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Gonçalves AS, Andrade N, Martel F. Intestinal fructose absorption: Modulation and relation to human diseases. PHARMANUTRITION 2020. [DOI: 10.1016/j.phanu.2020.100235] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
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Depletion of regulator-of-G-protein signaling-10 in mice exaggerates high-fat diet-induced insulin resistance and inflammation, and this effect is mitigated by dietary green tea extract. Nutr Res 2018; 70:50-59. [PMID: 30032988 DOI: 10.1016/j.nutres.2018.06.004] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2018] [Revised: 06/11/2018] [Accepted: 06/24/2018] [Indexed: 12/25/2022]
Abstract
The interaction between insulin resistance and inflammation plays a central role in the development of chronic diseases, although the mechanism is not fully understood. We previously demonstrated that regulator of G-protein signaling-10 (RGS10) protein is a negative modulator of the inflammatory response in macrophages and microglia. Because inflammation is a critical component in the development of high fat diet-induced insulin resistance, in this study we investigated whether RGS10 is involved in the diet-dependent regulation of glucose tolerance and insulin sensitivity. We hypothesized that the absence of RGS10 would exaggerate high-fat diet (HFD)-induced insulin resistance and inflammation response. Our results showed that RGS10 knockout (KO) mice fed a HFD gained significantly more weight and developed severe insulin resistance compared to wild-type (WT) mice fed HFD. Furthermore, compared to WT HFD-fed mice, KO mice fed the HFD displayed inflammatory phenotypes such as decreased adipose tissue expression of the anti-inflammatory M2 markers YM1 and Fizz1 and increased expression of the proinflammatory M1 cytokine interleukin 6 in adipose and CD11b, CD68 and interleukin 1β in liver tissues. The impact of RGS10 deficiency on the exaggeration of HFD-induced insulin resistance and inflammation was ameliorated by oral consumption of green tea extract. Our results demonstrate that RGS10 is an important part of a protective mechanism involved in in regulating metabolic homeostasis by reducing inflammatory responses, which could potentially lead to an innovative new approach targeting inflammation and insulin resistance.
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D'souza AM, Neumann UH, Glavas MM, Kieffer TJ. The glucoregulatory actions of leptin. Mol Metab 2017; 6:1052-1065. [PMID: 28951828 PMCID: PMC5605734 DOI: 10.1016/j.molmet.2017.04.011] [Citation(s) in RCA: 136] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/06/2017] [Revised: 04/18/2017] [Accepted: 04/24/2017] [Indexed: 12/28/2022] Open
Abstract
Background The hormone leptin is an important regulator of metabolic homeostasis, able to inhibit food intake and increase energy expenditure. Leptin can also independently lower blood glucose levels, particularly in hyperglycemic models of leptin or insulin deficiency. Despite significant efforts and relevance to diabetes, the mechanisms by which leptin acts to regulate blood glucose levels are not fully understood. Scope of review Here we assess literature relevant to the glucose lowering effects of leptin. Leptin receptors are widely expressed in multiple cell types, and we describe both peripheral and central effects of leptin that may be involved in lowering blood glucose. In addition, we summarize the potential clinical application of leptin in regulating glucose homeostasis. Major conclusions Leptin exerts a plethora of metabolic effects on various tissues including suppressing production of glucagon and corticosterone, increasing glucose uptake, and inhibiting hepatic glucose output. A more in-depth understanding of the mechanisms of the glucose-lowering actions of leptin may reveal new strategies to treat metabolic disorders.
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Affiliation(s)
- Anna M D'souza
- Department of Cellular and Physiological Sciences, University of British Columbia, 2350 Health Sciences Mall, Vancouver, British Columbia V6T 1Z3, Canada
| | - Ursula H Neumann
- Department of Cellular and Physiological Sciences, University of British Columbia, 2350 Health Sciences Mall, Vancouver, British Columbia V6T 1Z3, Canada
| | - Maria M Glavas
- Department of Cellular and Physiological Sciences, University of British Columbia, 2350 Health Sciences Mall, Vancouver, British Columbia V6T 1Z3, Canada
| | - Timothy J Kieffer
- Department of Cellular and Physiological Sciences, University of British Columbia, 2350 Health Sciences Mall, Vancouver, British Columbia V6T 1Z3, Canada.,Department of Surgery, University of British Columbia, 2350 Health Sciences Mall, Vancouver, British Columbia V6T 1Z3, Canada
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Alzamendi A, Zubiría G, Moreno G, Portales A, Spinedi E, Giovambattista A. High Risk of Metabolic and Adipose Tissue Dysfunctions in Adult Male Progeny, Due to Prenatal and Adulthood Malnutrition Induced by Fructose Rich Diet. Nutrients 2016; 8:178. [PMID: 27011203 PMCID: PMC4808904 DOI: 10.3390/nu8030178] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2015] [Revised: 02/29/2016] [Accepted: 03/14/2016] [Indexed: 12/18/2022] Open
Abstract
The aim of this work was to determine the effect of a fructose rich diet (FRD) consumed by the pregnant mother on the endocrine-metabolic and in vivo and in vitro adipose tissue (AT) functions of the male offspring in adulthood. At 60 days of age, rats born to FRD-fed mothers (F) showed impaired glucose tolerance after glucose overload and high circulating levels of leptin (LEP). Despite the diminished mass of retroperitoneal AT, this tissue was characterized by enhanced LEP gene expression, and hypertrophic adipocytes secreting in vitro larger amounts of LEP. Analyses of stromal vascular fraction composition by flow cytometry revealed a reduced number of adipocyte precursor cells. Additionally, 60 day-old control (C) and F male rats were subjected to control diet (CC and FC animals) or FRD (CF and FF rats) for three weeks. FF animals were heavier and consumed more calories. Their metabolic-endocrine parameters were aggravated; they developed severe hyperglycemia, hypertriglyceridemia, hyperleptinemia and augmented AT mass with hypertrophic adipocytes. Our study highlights that manipulation of maternal diet induced an offspring phenotype mainly imprinted with a severely unhealthy adipogenic process with undesirable endocrine-metabolic consequences, putting them at high risk for developing a diabetic state.
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Affiliation(s)
- Ana Alzamendi
- IMBICE (CICPBA-CONICET La Plata-National University of La Plata (UNLP)), La Plata 1900, Argentina.
| | - Guillermina Zubiría
- IMBICE (CICPBA-CONICET La Plata-National University of La Plata (UNLP)), La Plata 1900, Argentina.
| | - Griselda Moreno
- IIFP (CONICET La Plata) School of Exact Sciences, National University of La Plata (UNLP), La Plata1900, Argentina.
| | - Andrea Portales
- IMBICE (CICPBA-CONICET La Plata-National University of La Plata (UNLP)), La Plata 1900, Argentina.
| | - Eduardo Spinedi
- CENEXA (CONICET La Plata-UNLP, a PAHO/WHO (Collaborating Centre for Diabetes)), School of Medicine, National University of La Plata (UNLP), La Plata1900, Argentina.
| | - Andrés Giovambattista
- IMBICE (CICPBA-CONICET La Plata-National University of La Plata (UNLP)), La Plata 1900, Argentina.
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Ongaro L, Salvetti NR, Giovambattista A, Spinedi E, Ortega HH. Neonatal androgenization-induced early endocrine–metabolic and ovary misprogramming in the female rat. Life Sci 2015; 130:66-72. [DOI: 10.1016/j.lfs.2015.03.008] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2014] [Revised: 03/08/2015] [Accepted: 03/10/2015] [Indexed: 01/28/2023]
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Nomair AM, Aref NK, Rizwan F, Ezzo OH, Hassan N. Serum leptin level in obese women with polycystic ovary syndrome, and its relation to insulin resistance. ASIAN PACIFIC JOURNAL OF REPRODUCTION 2014. [DOI: 10.1016/s2305-0500(14)60041-5] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
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Borer KT. Counterregulation of insulin by leptin as key component of autonomic regulation of body weight. World J Diabetes 2014; 5:606-629. [PMID: 25317239 PMCID: PMC4138585 DOI: 10.4239/wjd.v5.i5.606] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/07/2013] [Revised: 05/15/2014] [Accepted: 06/03/2014] [Indexed: 02/05/2023] Open
Abstract
A re-examination of the mechanism controlling eating, locomotion, and metabolism prompts formulation of a new explanatory model containing five features: a coordinating joint role of the (1) autonomic nervous system (ANS); (2) the suprachiasmatic (SCN) master clock in counterbalancing parasympathetic digestive and absorptive functions and feeding with sympathetic locomotor and thermogenic energy expenditure within a circadian framework; (3) interaction of the ANS/SCN command with brain substrates of reward encompassing dopaminergic projections to ventral striatum and limbic and cortical forebrain. These drive the nonhomeostatic feeding and locomotor motivated behaviors in interaction with circulating ghrelin and lateral hypothalamic neurons signaling through melanin concentrating hormone and orexin-hypocretin peptides; (4) counterregulation of insulin by leptin of both gastric and adipose tissue origin through: potentiation by leptin of cholecystokinin-mediated satiation, inhibition of insulin secretion, suppression of insulin lipogenesis by leptin lipolysis, and modulation of peripheral tissue and brain sensitivity to insulin action. Thus weight-loss induced hypoleptimia raises insulin sensitivity and promotes its parasympathetic anabolic actions while obesity-induced hyperleptinemia supresses insulin lipogenic action; and (5) inhibition by leptin of bone mineral accrual suggesting that leptin may contribute to the maintenance of stability of skeletal, lean-body, as well as adipose tissue masses.
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Abstract
The fat‐derived hormone, leptin, is well known to regulate body weight. However, there is now substantial evidence that leptin also plays a primary role in the regulation of glucose homeostasis, independent of actions on food intake, energy expenditure or body weight. As such, leptin might have clinical utility in treating hyperglycemia, particularly in conditions of leptin deficiency, such as lipodystrophy and diabetes mellitus. The mechanisms through which leptin modulates glucose metabolism have not been fully elucidated. Leptin receptors are widely expressed in peripheral tissues, including the endocrine pancreas, liver, skeletal muscle and adipose, and both direct and indirect leptin action on these tissues contributes to the control of glucose homeostasis. Here we review the role of leptin in glucose homeostasis, along with our present understanding of the mechanisms involved. (J Diabetes Invest, doi: 10.1111/j.2040‐1124.2012.00203.x, 2012)
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Affiliation(s)
- Heather C Denroche
- Department of Cellular and Physiological Sciences, The Life Sciences Institute
| | - Frank K Huynh
- Department of Cellular and Physiological Sciences, The Life Sciences Institute
| | - Timothy J Kieffer
- Department of Cellular and Physiological Sciences, The Life Sciences Institute ; Department of Surgery, University of British Columbia, Vancouver, British Columbia, Canada
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Carter S, Caron A, Richard D, Picard F. Role of leptin resistance in the development of obesity in older patients. Clin Interv Aging 2013; 8:829-44. [PMID: 23869170 PMCID: PMC3706252 DOI: 10.2147/cia.s36367] [Citation(s) in RCA: 45] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
Abstract
Obesity is a global epidemic associated with aging-like cellular processes; in both aging and obesity, resistance to hormones such as insulin and leptin can be observed. Leptin is a circulating hormone/cytokine with central and peripheral effects that is released mainly by subcutaneous white adipose tissue. Centrally, leptin controls food intake, energy expenditure, and fat distribution, whereas it controls (among several others) insulin sensitivity, free fatty acids (FFAs) oxidation, and lipolysis in the periphery. Aging is associated with important changes in both the distribution and the composition of adipose tissue. Fat is redistributed from the subcutaneous to the visceral depot and increased inflammation participates in adipocyte dysfunction. This redistribution of adipose tissue in favor of visceral fat influences negatively both longevity and healthy aging as shown in numerous animal models. These modifications observed during aging are also associated with leptin resistance. This resistance blunts normal central and peripheral functions of leptin, which leads to a decrease in neuroendocrine function and insulin sensitivity, an imbalance in energy regulation, and disturbances in lipid metabolism. Here, we review how age-related leptin resistance triggers metabolic disturbances and affects the longevity of obese patients. Furthermore, we discuss the potential impacts of leptin resistance on the decline of brown adipose tissue thermogenesis observed in elderly individuals.
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Affiliation(s)
- Sophie Carter
- Faculty of Pharmacy, Department of Anatomy and Physiology, Université Laval, Québec, QC, Canada
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Harris RBS. Direct and indirect effects of leptin on adipocyte metabolism. Biochim Biophys Acta Mol Basis Dis 2013; 1842:414-23. [PMID: 23685313 DOI: 10.1016/j.bbadis.2013.05.009] [Citation(s) in RCA: 200] [Impact Index Per Article: 16.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2013] [Revised: 04/18/2013] [Accepted: 05/06/2013] [Indexed: 12/22/2022]
Abstract
Leptin is hypothesized to function as a negative feedback signal in the regulation of energy balance. It is produced primarily by adipose tissue and circulating concentrations correlate with the size of body fat stores. Administration of exogenous leptin to normal weight, leptin responsive animals inhibits food intake and reduces the size of body fat stores whereas mice that are deficient in either leptin or functional leptin receptors are hyperphagic and obese, consistent with a role for leptin in the control of body weight. This review discusses the effect of leptin on adipocyte metabolism. Because adipocytes express leptin receptors there is the potential for leptin to influence adipocyte metabolism directly. Adipocytes also are insulin responsive and receive sympathetic innervation, therefore leptin can also modify adipocyte metabolism indirectly. Studies published to date suggest that direct activation of adipocyte leptin receptors has little effect on cell metabolism in vivo, but that leptin modifies adipocyte sensitivity to insulin to inhibit lipid accumulation. In vivo administration of leptin leads to a suppression of lipogenesis, an increase in triglyceride hydrolysis and an increase in fatty acid and glucose oxidation. Activation of central leptin receptors also contributes to the development of a catabolic state in adipocytes, but this may vary between different fat depots. Leptin reduces the size of white fat depots by inhibiting cell proliferation both through induction of inhibitory circulating factors and by contributing to sympathetic tone which suppresses adipocyte proliferation. This article is part of a Special Issue entitled: Modulation of Adipose Tissue in Health and Disease.
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Affiliation(s)
- Ruth B S Harris
- Department of Physiology, Medical College of Georgia, Georgia Regents University, USA.
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Antioxidant treatment prevents the development of fructose-induced abdominal adipose tissue dysfunction. Clin Sci (Lond) 2013; 125:87-97. [DOI: 10.1042/cs20120470] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
In the present study, we tested the effect of OS (oxidative stress) inhibition in rats fed on an FRD [fructose-rich diet; 10% (w/v) in drinking water] for 3 weeks. Normal adult male rats received a standard CD (commercial diet) or an FRD without or with an inhibitor of NADPH oxidase, APO (apocynin; 5 mM in drinking water; CD-APO and FRD-APO). We thereafter measured plasma OS and metabolic-endocrine markers, AAT (abdominal adipose tissue) mass and cell size, FA (fatty acid) composition (content and release), OS status, LEP (leptin) and IRS (insulin receptor substrate)-1/IRS-2 mRNAs, ROS (reactive oxygen species) production, NADPH oxidase activity and LEP release by isolated AAT adipocytes. FRD-fed rats had larger AAT mass without changes in body weight, and higher plasma levels of TAG (triacylglycerol), FAs, TBARS (thiobarbituric acid-reactive substance) and LEP. Although no significant changes in glucose and insulin plasma levels were observed in these animals, their HOMA-IR (homoeostasis model assessment of insulin resistance) values were significantly higher than those of CD. The AAT from FRD-fed rats had larger adipocytes, higher saturated FA content, higher NADPH oxidase activity, greater ROS production, a distorted FA content/release pattern, lower insulin sensitivity together with higher and lower mRNA content of LEP and IRS-1-/2 respectively, and released a larger amount of LEP. The development of all the clinical, OS, metabolic, endocrine and molecular changes induced by the FRD were significantly prevented by APO co-administration. The fact that APO treatment prevented both changes in NADPH oxidase activity and the development of all the FRD-induced AAT dysfunctions in normal rats strongly suggests that OS plays an important role in the FRD-induced MS (metabolic syndrome) phenotype.
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Effect of pioglitazone on the fructose-induced abdominal adipose tissue dysfunction. PPAR Res 2012; 2012:259093. [PMID: 23091482 PMCID: PMC3469242 DOI: 10.1155/2012/259093] [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: 05/23/2012] [Accepted: 08/23/2012] [Indexed: 12/31/2022] Open
Abstract
Aim. To test the potential role of PPARγ in the endocrine abdominal tissue dysfunction induced by feeding normal rats with a fructose rich diet (FRD) during three weeks. Methodology. Adult normal male rats received a standard commercial diet (CD) or FRD, (10% in drinking water) without or with pioglitazone (PIO) (i.p. 0.25 mg/Kg BW/day; CD-PIO and FRD-PIO). Thereafter, we measured circulating metabolic, endocrine, and oxidative stress (OS) markers, abdominal adipose tissue (AAT) mass, leptin (LEP) and plasminogen activator inhibitor-1 (PAI-1) tissue content/expression, and leptin release by isolated adipocytes incubated with different concentrations of insulin. Results. Plasma glucose, insulin, triglyceride, TBARS, LEP, and PAI-1 levels were higher in FRD rats; PIO coadministration fully prevented all these increments. AAT adipocytes from FRD rats were larger, secreted a higher amount of LEP, and displayed decreased sensitivity to insulin stimulation; these effects were significantly ameliorated by PIO. Whereas AAT LEP and PAI-1 (mRNA) concentrations increased significantly in FRD rats, those of insulin-receptor-substrate- (IRS-) 1 and IRS-2 were reduced. PIO coadministration prevented FRD effects on LEP, PAI-1, and IRS-2 (fully) and IRS-1 (partially) mRNAs in AAT. Conclusion. PPARγ would play a relevant role in the development of the FRD-induced metabolic-endocrine dysfunction.
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Fructose rich diet-induced high plasminogen activator inhibitor-1 (PAI-1) production in the adult female rat: protective effect of progesterone. Nutrients 2012; 4:1137-50. [PMID: 23016136 PMCID: PMC3448091 DOI: 10.3390/nu4081137] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2012] [Revised: 07/20/2012] [Accepted: 08/08/2012] [Indexed: 11/18/2022] Open
Abstract
The effect of progesterone (P4) on fructose rich diet (FRD) intake-induced metabolic, endocrine and parametrial adipose tissue (PMAT) dysfunctions was studied in the adult female rat. Sixty day-old rats were i.m. treated with oil alone (control, CT) or containing P4 (12 mg/kg). Rats ate Purina chow-diet ad libitum throughout the entire experiment and, between 100 and 120 days of age drank ad libitum tap water alone (normal diet; CT-ND and P4-ND) or containing fructose (10% w/v; CT-FRD and P4-FRD). At age 120 days, animals were subjected to a glucose tolerance test or decapitated. Plasma concentrations of various biomarkers and PMAT gene abundance were monitored. P4-ND (vs. CT-ND) rats showed elevated circulating levels of lipids. CT-FRD rats displayed high (vs. CT-ND) plasma concentrations of lipids, leptin, adiponectin and plasminogen activator inhibitor-1 (PAI-1). Lipidemia and adiponectinemia were high (vs. P4-ND) in P4-FRD rats. Although P4 failed to prevent FRD-induced hyperleptinemia, it was fully protective on FRD-enhanced plasma PAI-1 levels. PMAT leptin and adiponectin mRNAs were high in CT-FRD and P4-FRD rats. While FRD enhanced PMAT PAI-1 mRNA abundance in CT rats, this effect was absent in P4 rats. Our study supports that a preceding P4-enriched milieu prevented the enhanced prothrombotic risk induced by FRD-elicited high PAI-1 production.
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Mantzoros CS, Magkos F, Brinkoetter M, Sienkiewicz E, Dardeno TA, Kim SY, Hamnvik OPR, Koniaris A. Leptin in human physiology and pathophysiology. Am J Physiol Endocrinol Metab 2011; 301:E567-84. [PMID: 21791620 PMCID: PMC3191548 DOI: 10.1152/ajpendo.00315.2011] [Citation(s) in RCA: 403] [Impact Index Per Article: 28.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Leptin, discovered through positional cloning 15 years ago, is an adipocyte-secreted hormone with pleiotropic effects in the physiology and pathophysiology of energy homeostasis, endocrinology, and metabolism. Studies in vitro and in animal models highlight the potential for leptin to regulate a number of physiological functions. Available evidence from human studies indicates that leptin has a mainly permissive role, with leptin administration being effective in states of leptin deficiency, less effective in states of leptin adequacy, and largely ineffective in states of leptin excess. Results from interventional studies in humans demonstrate that leptin administration in subjects with congenital complete leptin deficiency or subjects with partial leptin deficiency (subjects with lipoatrophy, congenital or related to HIV infection, and women with hypothalamic amenorrhea) reverses the energy homeostasis and neuroendocrine and metabolic abnormalities associated with these conditions. More specifically, in women with hypothalamic amenorrhea, leptin helps restore abnormalities in hypothalamic-pituitary-peripheral axes including the gonadal, thyroid, growth hormone, and to a lesser extent adrenal axes. Furthermore, leptin results in resumption of menses in the majority of these subjects and, in the long term, may increase bone mineral content and density, especially at the lumbar spine. In patients with congenital or HIV-related lipoatrophy, leptin treatment is also associated with improvements in insulin sensitivity and lipid profile, concomitant with reduced visceral and ectopic fat deposition. In contrast, leptin's effects are largely absent in the obese hyperleptinemic state, probably due to leptin resistance or tolerance. Hence, another emerging area of research pertains to the discovery and/or usefulness of leptin sensitizers. Results from ongoing studies are expected to further increase our understanding of the role of leptin and the potential clinical applications of leptin or its analogs in human therapeutics.
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Affiliation(s)
- Christos S Mantzoros
- Division of Endocrinology, Diabetes and Metabolism, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
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Yadav A, Jyoti P, Jain SK, Bhattacharjee J. Correlation of adiponectin and leptin with insulin resistance: a pilot study in healthy north Indian population. Indian J Clin Biochem 2011; 26:193-6. [PMID: 22468049 DOI: 10.1007/s12291-011-0119-1] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2010] [Accepted: 01/24/2011] [Indexed: 10/18/2022]
Abstract
The increasing incidence of obesity, leading to metabolic complications is now recognized as a major public-health problem. Insulin resistance is a central abnormality of the metabolic syndrome, or syndrome X, originally hypothesized by Reaven Insulin resistance is more strongly linked to intra abdominal fat than to fat in other depots. Adipose tissue secretes numerous factors (adipokines) known to markedly influence lipid and glucose/insulin metabolism, oxidative stress, and cardiovascular integrity. Some of these adipokines have been shown to directly or indirectly affect insulin sensitivity through modulation of insulin signaling and the molecules involved in glucose and lipid metabolism. A pilot study was conducted with 80 healthy subjects who were non diabetic, non hypertensive and having no family history of hypertension, the aim was to evaluate the correlation of adiponectin and leptin levels with obesity and insulin resistance markers in healthy north Indian adult population. Serum leptin, adiponectin and insulin was estimated by sandwich ELISA method. In our study, Leptin correlated significantly with BMI (P value of 0.0000), WC (P value = 0.007), and HC (P value = 0.000). leptin showed significant positive correlation with fasting insulin (P value 0.002), post prandial insulin (P value = 0.000) and HOMA-IR (P value = 0.002). Adiponectin showed significant positive correlation with triglycerides (P value = 0.038), strong negative correlation with HDL-cholesterol (P value = 0.017). Serum concentrations of leptin are associated with central body fat distribution. Insulin resistance and adiponectin is associated with dyslipidemia and these all disorders may ultimately lead to metabolic syndrome.
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Alzamendi A, Castrogiovanni D, Gaillard RC, Spinedi E, Giovambattista A. Increased male offspring's risk of metabolic-neuroendocrine dysfunction and overweight after fructose-rich diet intake by the lactating mother. Endocrinology 2010; 151:4214-23. [PMID: 20660072 DOI: 10.1210/en.2009-1353] [Citation(s) in RCA: 45] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
An adverse endogenous environment during early life predisposes the organism to develop metabolic disorders. We evaluated the impact of intake of an iso-caloric fructose rich diet (FRD) by lactating mothers (LM) on several metabolic functions of their male offspring. On postnatal d 1, ad libitum eating, lactating Sprague-Dawley rats received either 10% F (wt/vol; FRD-LM) or tap water (controls, CTR-LM) to drink throughout lactation. Weaned male offspring were fed ad libitum a normal diet, and body weight (BW) and food intake were registered until experimentation (60 d of age). Basal circulating levels of metabolic markers were evaluated. Both iv glucose tolerance and hypothalamic leptin sensitivity tests were performed. The hypothalamus was dissected for isolation of total RNA and Western blot analysis. Retroperitoneal (RP) adipose tissue was dissected and either kept frozen for gene analysis or digested to isolate adipocytes or for histological studies. FRD rats showed increased BW and decreased hypothalamic sensitivity to exogenous leptin, enhanced food intake (between 49-60 d), and decreased hypothalamic expression of several anorexigenic signals. FRD rats developed increased insulin and leptin peripheral levels and decreased adiponectinemia; although FRD rats normally tolerated glucose excess, it was associated with enhanced insulin secretion. FRD RP adipocytes were enlarged and spontaneously released high leptin, although they were less sensitive to insulin-induced leptin release. Accordingly, RP fat leptin gene expression was high in FRD rats. Excessive fructose consumption by lactating mothers resulted in deep neuroendocrine-metabolic disorders of their male offspring, probably enhancing the susceptibility to develop overweight/obesity during adult life.
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Affiliation(s)
- Ana Alzamendi
- Neuroendocrine Unit, Instituto Multidisciplinario de Biología Celular, (Consejo Nacional de Investigaciones Científicas y Técnicas-Comisión de Investigaciones Científicas de la Prov. de Buenos Aires), 1900 La Plata, Argentina
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Alzamendi A, Castrogiovanni D, Ortega HH, Gaillard RC, Giovambattista A, Spinedi E. Parametrial adipose tissue and metabolic dysfunctions induced by fructose-rich diet in normal and neonatal-androgenized adult female rats. Obesity (Silver Spring) 2010; 18:441-8. [PMID: 19696763 DOI: 10.1038/oby.2009.255] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Hyperandrogenemia predisposes an organism toward developing impaired insulin sensitivity. The aim of our study was to evaluate endocrine and metabolic effects during early allostasis induced by a fructose-rich diet (FRD) in normal (control; CT) and neonatal-androgenized (testosterone propionate; TP) female adult rats. CT and TP rats were fed either a normal diet (ND) or an FRD for 3 weeks immediately before the day of study, which was at age 100 days. Energy intake, body weight (BW), parametrial (PM) fat characteristics, and endocrine/metabolic biomarkers were then evaluated. Daily energy intake was similar in CT and TP rats regardless of the differences in diet. When compared with CT-ND rats, the TP-ND rats were heavier, had larger PM fat, and were characterized by basal hypoadiponectinemia and enhanced plasma levels of non-esterified fatty acid (NEFA), plasminogen activator inhibitor-1 (PAI-1), and leptin. FRD-fed CT rats, when compared with CT-ND rats, had high plasma levels of NEFA, triglyceride (TG), PAI-1, leptin, and adiponectin. The TP-FRD rats, when compared with TP-ND rats, displayed enhanced leptinemia and triglyceridemia, and were hyperinsulinemic, with glucose intolerance. The PM fat taken from TP rats displayed increase in the size of adipocytes, decrease in adiponectin (protein/gene), and a greater abundance of the leptin gene. PM adipocyte response to insulin was impaired in CT-FRD, TP-ND, and TP-FRD rats. A very short duration of isocaloric FRD intake in TP rats induced severe metabolic dysfunction at the reproductive age. Our study supports the hypothesis that the early-androgenized female rat phenotype is highly susceptible to developing endocrine/metabolic dysfunction. In turn, these abnormalities enhance the risk of metabolic syndrome, obesity, type 2 diabetes, and cardiovascular disease.
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Affiliation(s)
- Ana Alzamendi
- Neuroendocrine Unit, IMBICE (CONICET-CICPBA), La Plata, Argentina
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Lago F, Gómez R, Gómez-Reino JJ, Dieguez C, Gualillo O. Adipokines as novel modulators of lipid metabolism. Trends Biochem Sci 2009; 34:500-10. [PMID: 19729309 DOI: 10.1016/j.tibs.2009.06.008] [Citation(s) in RCA: 140] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2009] [Revised: 05/22/2009] [Accepted: 06/04/2009] [Indexed: 01/20/2023]
Abstract
In the mid-1990s, interest in adipose tissue - until then generally regarded as a mere energy reserve - was revived by the discovery of leptin. Since then numerous other cytokine-like hormones have been isolated from white adipose tissue. These adipokines have been investigated in relation to obesity, metabolic syndrome, insulin resistance and other pathological conditions and processes. In addition, it is now established that adipokines play a role in the maintenance of an inflammatory state in adipose tissue and in the development of obesity and comorbidities. The contributions of individual adipokines in the pathophysiological features of obesity have yet to be determined in full, but recent data highlight important roles for adipokines in lipid metabolism.
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Affiliation(s)
- Francisca Lago
- Research Laboratory 7 (Molecular and Cellular Cardiology), Institute of Medical Research (IDIS), University Clinical Hospital, Santiago de Compostela 15706, Spain.
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Alzamendi A, Giovambattista A, Raschia A, Madrid V, Gaillard RC, Rebolledo O, Gagliardino JJ, Spinedi E. Fructose-rich diet-induced abdominal adipose tissue endocrine dysfunction in normal male rats. Endocrine 2009; 35:227-32. [PMID: 19165636 DOI: 10.1007/s12020-008-9143-1] [Citation(s) in RCA: 52] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/26/2008] [Revised: 11/07/2008] [Accepted: 12/17/2008] [Indexed: 12/12/2022]
Abstract
We have currently studied the changes induced by administration of a fructose-rich diet (FRD) to normal rats in the mass and the endocrine function of abdominal (omental) adipose tissue (AAT). Rats were fed ad libitum a standard commercial chow and tap water, either alone (control diet, CD) or containing fructose (10%, w/vol) (FRD). Three weeks after treatment, circulating metabolic markers and leptin release from adipocytes of AAT were measured. Plasma free fatty acids (FFAs), leptin, adiponectin, and plasminogen activator inhibitor-1 (PAI-1) levels were significantly higher in FRD than in CD rats. AAT mass was greater in FRD than in CD rats and their adipocytes were larger, they secreted more leptin and showed impaired insulin sensitivity. While leptin mRNA expression increased in AAT from FRD rats, gene expression of insulin receptor substrate, IRS1 and IRS2 was significantly reduced. Our study demonstrates that administration of a FRD significantly affects insulin sensitivity and several AAT endocrine/metabolic functions. These alterations could be part of a network of interacting abnormalities triggered by FRD-induced oxidative stress at the AAT level. In view of the impaired glucose tolerance observed in FRD rats, these alterations could play a key role in both the development of metabolic syndrome (MS) and beta-cell failure.
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Affiliation(s)
- Ana Alzamendi
- Neuroendocrine Unit, IMBICE (CONICET-CICPBA), 1900 La Plata, Argentina
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Russell JC, Proctor SD, Kelly SE, Brindley DN. Pair feeding-mediated changes in metabolism: stress response and pathophysiology in insulin-resistant, atherosclerosis-prone JCR:LA-cp rats. Am J Physiol Endocrinol Metab 2008; 294:E1078-87. [PMID: 18413677 DOI: 10.1152/ajpendo.90257.2008] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Rats of the JCR:LA-cp strain, which are homozygous for the cp gene (cp/cp), are obese, insulin-resistant, and hyperinsulinemic. They exhibit associated micro- and macrovascular disease and end-stage ischemic myocardial lesions and are highly stress sensitive. We subjected male cp/cp rats to pair feeding (providing the rats each day with the amount of food eaten by matched freely fed animals), a procedure that alters the diurnal feeding pattern, leading to a state of intermittent caloric restriction. Effects on insulin, glucose, and lipid metabolism, response to restraint stress, aortic contractile/relaxant response, and myocardial lesion frequency were investigated. Pair-fed young (12-wk-old) cp/cp rats had lower insulin and glucose levels (basal and following restraint), consistent with increased insulin sensitivity, but a greater increase in plasma nonesterified fatty acids in response to restraint. These effects were unrelated to lipolytic rates in adipose tissue but may be related to reduced fatty acid oxidation in skeletal muscle. Older (24-wk-old) pair-fed cp/cp rats had significantly reduced plasma triglyceride levels, improved micro- and macrovascular function, and reduced severity of ischemic myocardial lesions. These changes indicate a significant amelioration of end-stage disease processes in this animal model and the complexity of metabolic/physiological responses in studies involving alterations in food intake. The effects illustrate the sensitivity of the JCR:LA-cp rat, an animal model for the metabolic syndrome and associated cardiovascular disease, to the environmental and experimental milieu. Similar stress-related mechanisms may play a role in metabolically induced cardiovascular disease in susceptible human beings.
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Affiliation(s)
- James C Russell
- Metabolic and Cardiovascular Diseases Laboratory, Alberta Institute for Human Nutrition, University of Alberta, Edmonton, AB, Canada.
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23
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Perello M, Castrogiovanni D, Giovambattista A, Gaillard RC, Spinedi E. Impairment in insulin sensitivity after early androgenization in the post-pubertal female rat. Life Sci 2007; 80:1792-8. [PMID: 17368679 DOI: 10.1016/j.lfs.2007.02.013] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2006] [Revised: 01/24/2007] [Accepted: 02/07/2007] [Indexed: 01/09/2023]
Abstract
A link is known to exist between hyperandrogenicity and insulin resistance in mammals. We explored whether androgenization, early in reproductive life, in the female rat has any impact on later peripheral insulin sensitivity and parametrial (PM) fat function. Female, 60 day-old, rats were injected (i.m.) with 100 mul of sterile corn oil either alone (CT) or containing 2 mg of testosterone propionate (TP); rats were then used for experimentation at age 120 days. Daily food intake and body weight were recorded. Different groups of CT and TP rats were subjected to a high glucose load test or 24 h fasting for evaluation of changes in circulating levels of several metabolites and body composition. In vitro experiments were run to study the impact of androgenization on isolated PM adipocyte response to insulin. Finally, the direct effect of testosterone on insulin-induced leptin secretion by normal PM adipocytes was also evaluated. Androgenization induced a significant increase in daily food intake and body weight for the first 20 days after treatment. In vivo experiments indicate that TP rats released more (P<0.05) insulin than CT animals after high glucose load in order to maintain similar circulating glucose levels, a characteristic accompanied by decreased (P<0.05) overall corticoadrenal response in TP rats. Several metabolic responses to fasting were similar in both groups, although impaired adrenal response and changes in body composition were observed only in TP rats. Interestingly, cultured PM adipocytes from TP rats were less (P<0.05) sensitive than CT cells to insulin-induced leptin secretion. Also, we found that 48 h exposure of normal PM adipocytes to high testosterone concentration also impaired adipocyte endocrine function. Our study strongly supports that development of insulin resistance, in the female gender, can be established after an early, even transient, hyperandrogenemia.
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Affiliation(s)
- Mario Perello
- Neuorendocrine Unit, IMBICE (CONICET-CICPBA), 1900 La Plata, Argentina
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24
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Carraro R, Ruiz-Torres A. Relationship of serum leptin concentration with age, gender, and biomedical parameters in healthy, non-obese subjects. Arch Gerontol Geriatr 2006; 43:301-12. [PMID: 16448711 DOI: 10.1016/j.archger.2005.11.004] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2005] [Revised: 11/17/2005] [Accepted: 11/18/2005] [Indexed: 11/30/2022]
Abstract
It is known that the circulating levels of leptin, the adipocyte hormone implicated in the control of energy balance, are correlated with fat body mass (FBM), although the influences of other physiological conditions are not fully understood. We investigated the relationships of serum leptin concentration with age, gender, and 36 hormone-metabolic parameters in a sample of a well defined healthy population (n=246; age range 20-93 years), and in subgroups of lean individuals according to their body mass index (BMI), within similar age range and gender distribution. Only insulin secretion (positively) and testosteronemia (negatively, in males) show direct correlations. The other relationships are not significant but throughout collaborating variables, such as serum lipids, especially through FBM, lean body mass (LBM) through insulin secretion, and gender through FBM. In males, LBM correlates with insulin secretions, s-IGF-1 and with s-testosterone. The relationship between insulin secretion and LBM persists up to advanced age. From the present study it may be concluded that the positive relationship of leptin with insulin secretion and the negative one with testosterone, indicate direct implications of leptin in insulin signaling, as well as in male sexual development. Finally, the fact that the amount of secreted insulin depends on LBM and the latter on testosterone and IGF-1, indicates the importance of muscle mass in the control of insulin secretion.
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Affiliation(s)
- R Carraro
- University Institute for Aging and Metabolic Research (IUIGM), Autonomous University of Madrid, Hospital de la Princesa, C/Diego de León, 62, 28006 Madrid, Spain
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Abstract
Obesity and the metabolic syndrome have both reached pandemic proportions. Together they have the potential to impact on the incidence and severity of cardiovascular pathologies, with grave implications for worldwide health care systems. The metabolic syndrome is characterized by visceral obesity, insulin resistance, hypertension, chronic inflammation, and thrombotic disorders contributing to endothelial dysfunction and, subsequently, to accelerated atherosclerosis. Obesity is a key component in development of the metabolic syndrome and it is becoming increasingly clear that a central factor in this is the production by adipose cells of bioactive substances that directly influence insulin sensitivity and vascular injury. In this paper, we review advances in the understanding of biologically active molecules collectively referred to as "adipokines" and how dysregulated production of these factors in obese states mediates the pathogenesis of obesity associated metabolic syndrome.
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Affiliation(s)
- Louise Hutley
- Centre for Diabetes and Endocrine Research, University of Queensland, Australia
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Della-Fera MA, Baile CA. Roles for melanocortins and leptin in adipose tissue apoptosis and fat deposition. Peptides 2005; 26:1782-7. [PMID: 16002187 DOI: 10.1016/j.peptides.2004.12.023] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/30/2004] [Accepted: 12/12/2004] [Indexed: 10/25/2022]
Abstract
Leptin has a wide range of effects on physiological functions related to the regulation of body energy balance. Many of leptin's effects are mediated through neuropeptide-containing neurons and neuropeptide receptors in the hypothalamus. The melanocortin system includes both agonist (alpha-melanocyte stimulating hormone, alphaMSH) and antagonist peptides (agouti related peptide, AGRP). Increased melanocortin receptor stimulation following leptin administration plays an important role in leptin-induced hypophagia and increased sympathetic nervous system activity and is partly responsible for leptin-induced weight loss. However, melanocortins do not appear to mediate some of the more striking centrally-mediated effects of leptin on adipose tissue, including adipose tissue apoptosis, that lead to the extensive depletion of fat.
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Affiliation(s)
- Mary Anne Della-Fera
- Department of Animal and Dairy Science, University of Georgia, 444 Animal Science Complex, Athens, GA 30602-2771, USA
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27
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Ceddia RB. Direct metabolic regulation in skeletal muscle and fat tissue by leptin: implications for glucose and fatty acids homeostasis. Int J Obes (Lond) 2005; 29:1175-83. [PMID: 16030519 DOI: 10.1038/sj.ijo.0803025] [Citation(s) in RCA: 115] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
In recent years, the adipose tissue has emerged as an important endocrine organ. It is now recognized that besides storing energy the adipocytes also secrete several bioactive peptides, collectively called adipocytokines. Among these adipocytokines, leptin, the product of the ob gene, has been extensively investigated over the last decade. Skeletal muscle and adipose tissue, two major tissues involved in the regulation of glucose and fatty acids metabolism, have been consistently demonstrated to be directly affected by leptin. By binding to its receptors located in skeletal muscle and fat cells, leptin promotes energy dissipation and prevents fatty acid accumulation and 'lipotoxicity' in these tissues. On the other hand, under conditions of peripheral leptin resistance, such as observed in obese humans, the activation of pathways involved in fatty acid oxidation may be impaired. This leads to intracellular accumulation of lipid intermediates and causes insulin resistance. This review examines the metabolic pathways that are directly activated by leptin and how it regulates glucose and fatty acids metabolism in skeletal muscle and fat tissue. Furthermore, the impact of peripheral leptin resistance in these tissues leading to dysfunctional metabolic adaptations is also discussed.
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Affiliation(s)
- R B Ceddia
- Department of Kinesiology and Health Science, York University, Toronto, Ontario, Canada.
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Saleh HA, El-Nwaem MA, El-Bordiny MM, Maqlad HMES, El-Mohandes AA, Eldaqaq EM. Serum leptin elevation in obese women with PCOs: a continuing controversy. J Assist Reprod Genet 2005; 21:361-6. [PMID: 15587140 PMCID: PMC3455233 DOI: 10.1023/b:jarg.0000046204.81682.67] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
PURPOSE To evaluate leptin levels in a sample of obese women with PCOS and compare the results with obese and non-obese control, to be ultimately correlated with BMI, and insulin sensitivity. METHODS Leptin and insulin assays by immuno-radiometric method, glucose assay by enzymatic colorimetric method. RESULTS Leptin levels were significantly different between obese and non-obese subjects, and were significantly different between insulin resistant and non-insulin resistant obese PCOS, but were not significantly different between obese non-insulin resistant PCOS, and obese controls. CONCLUSIONS Body mass index and insulin resistance are the two main factors governing serum leptin levels.
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Affiliation(s)
- Hisham Ali Saleh
- Department of Obstetrics and Gynecology, Faculty of Medicine, Alexandria University, Alexandria, Egypt.
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Abstract
The present study examined whether recombinant porcine leptin alters lipid synthesis in porcine adipocytes. The stromal-vascular cell fraction of neonatal pig subcutaneous adipose tissue was isolated by collagenase digestion, filtration, and subsequent centrifugation. These cells were seeded on 25-cm2 tissue culture flasks and proliferated to confluency in 10% (vol/vol) fetal bovine serum in Dulbecco's modified Eagle medium/F12 (DMEM/F12, 50:50). Cultures were differentiated using 2.5% pig serum (vol/vol), 10 nM insulin, 100 nM hydrocortisone. After 7 d of lipid filling, cultures were washed free of this medium, incubated overnight in DMEM/F12 containing 2% pig serum (vol/vol), and then used for experiments. Acute experiments assessed U-(14)C-glucose or 1-(14)C-palmitate metabolism in cultures exposed to porcine leptin (0 to 1,000 ng/mL medium) for 4 h. Chronic experiments used cultures incubated with 0 to 1,000 ng porcine leptin/mL medium for 44 h before measurements of U-(14)C-glucose and 1-(14)C-palmitate oxidation and incorporation into lipid. Another experiment examined whether chronic leptin treatment alters insulin responsiveness by including insulin (10 nM) with incubations containing leptin. Leptin had no acute effects on glucose oxidation or conversion to lipid (P > 0.05). Acute leptin treatment decreased palmitate incorporation into lipids up to 45% (P < 0.05). Chronic leptin exposure decreased glucose oxidation (21%), total lipid synthesis (18%), and fatty acid synthesis (23%) at 100 ng/mL medium (P < 0.05). Insulin increased rates of glucose oxidation, total lipid, and fatty acid synthesis (P < 0.05); however, chronic exposure to 10 ng leptin/mL medium decreased the effectiveness of 10 nM insulin to affect these measures of glucose metabolism by approximately 18 to 46% (P < 0.05). Higher concentrations of leptin inhibited all effects of insulin on glucose metabolism (P < 0.05). Chronic exposure to leptin increased palmitate oxidation by 36% (P < 0.05). Chronic leptin exposure decreased palmitate incorporation into total lipids by 40% at 100 ng/mL medium (P < 0.05). Lipoprotein lipase activity was not affected (P > 0.05) by leptin. These data indicate that leptin functions to promote partitioning of energy away from lipid accretion within porcine adipose tissue by inhibiting glucose oxidation and lipogenesis indirectly, by decreasing insulin-mediated stimulation of lipogenesis, and by stimulating fatty acid oxidation while inhibiting fatty acid esterification.
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Affiliation(s)
- T G Ramsay
- Growth Biology Laboratory, USDA-ARS, Beltsville, MD 20705, USA.
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Tene Pérez CE, Revilla-Monsalve MC, Amato D, Escobedo de la Peña J, Galván R, Millán-Guerrero RO, Trujillo Hernández B, Zárate A, Islas-Andrade S. Correlation between serum leptin levels and insulin sensitivity in diffuse toxic goiter. Endocr Res 2004; 30:19-27. [PMID: 15098916 DOI: 10.1081/erc-120028384] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/03/2022]
Abstract
OBJECTIVE The aim of this survey was to assess the correlation between leptin and insulin sensitivity (IS) in cases of diffuse toxic goiter. DESIGN, PATIENTS, MEASUREMENTS This is a descriptive study on patients with diffuse toxic goiter (DTG) assessing their body mass index (BMI), serum leptin concentrations, circulating insulin (area under the curve (AuC) of insulin), average insulin level, thyroid hormones, thyroid stimulating hormone (TSH), glycemia and IS (using a hyperinsulinemic-euglycemic clamp and the homeostasis model for assessment of insulin resistance (HOMA-IR) before and after euthyroidism induced with metimazol. RESULTS The average patient age was 35 years old (range 31-40 years), height was 157 cm (range 151-160 cm), glycemia was 4.3 +/- 0.3 mmol/L and TSH 0.1 +/- 0.1 microU/mL. Average leptin level was 11.3 +/- 2.8 ng/dL, the average insulin level was 10.13 +/- 3.7 mIU/mL and the AuC for insulin was 50.6 +/- 18 microIU x min/mL. No correlation was found between leptin and BMI, thyroid hormones and glycemia. While controlling for the BMI effect, a correlation was found between leptin and TSH (r = -0.77, p = 0.042), as well as between leptin and insulinemia (r = 0.93, r2 = 0.86, p = 0.001) independently from the state of thyroid function. There was a tendency for a high correlation between leptin and the insulin AuC (hyperthyroidism: r = 0.89, p = 0.056; euthyroidism: r = 0.99, p = 0.056). A negative correlation was found between IS and the insulin AuC (rho = -0.58, p = 0.18). There was a high tendency for correlation between leptin and IS when the BMI effect (HOMA-IR: r = 0.70, p = 0.12; PHE: r = -0.55, p = 0.26) was taken into consideration. CONCLUSIONS There is a high tendency for a negative correlation between leptin and IS when the BMI effect is controlled. There is a high tendency for a positive correlation between leptin and insulin and TSH.
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Affiliation(s)
- C E Tene Pérez
- Medical Research Unit in Clinical Epidemiology, Family Medicine Zone General Hospital No. 1, Mexican Institute of Social Security, Colima, Mexico.
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Abstract
This study examined if leptin can acutely affect glucose or fatty acid metabolism in pig adipocytes and whether leptin's actions on lipogenesis are manifested through interaction with insulin or growth hormone. Subcutaneous adipose tissue was obtained from approximately 55 kg crossbred barrows at the USDA abattoir. Isolated adipocytes were prepared using a collagenase procedure. Experiments assessed U-14C-glucose or 1-14C-palmitate metabolism in isolated adipocytes exposed to: basal medium (control), 100 nM insulin, 100 ng/ml porcine growth hormone, 100 ng/ml recombinant porcine leptin, and combinations of these hormones. Treatments were performed in triplicate and the experiment was repeated with adipocytes isolated from five different animals. Cell aliquots (250 microl) were added to 1 ml of incubation medium, then incubated for 2h at 37 degrees C for measurement of glucose and palmitate oxidation or incorporation into lipid. Incubation of isolated adipocytes with insulin increased glucose oxidation rate by 18% (P<0.05), while neither growth hormone nor leptin affected glucose oxidation (P>0.5). Total lipid synthesis from glucose was increased by approximately 25% by 100 nM insulin or insulin+growth hormone (P<0.05). Insulin+leptin reduced the insulin response by 37% (P<0.05). The combination of all three hormones increased total lipid synthesis by 35%, relative to controls (P<0.05), a rate similar to insulin alone. Fatty acid synthesis was elevated by insulin (32%, P<0.05) or growth hormone (13%, P<0.05). Leptin had no effect on fatty acid synthesis (P>0.05). Leptin reduced the esterification rate by 10% (P<0.05). Growth hormone and insulin could overcome leptin's inhibition of palmitate esterification (P>0.05).
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Affiliation(s)
- Timothy G Ramsay
- Growth Biology Laboratory, USDA-ARS, BARC-East, Bldg. 200, Rm. 201, Beltsville, MD 20705, USA.
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32
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Balasubramaniyan V, Nalini N. The potential beneficial effect of leptin on an experimental model of hyperlipidemia, induced by chronic ethanol treatment. Clin Chim Acta 2003; 337:85-91. [PMID: 14568184 DOI: 10.1016/j.cccn.2003.07.004] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
BACKGROUND Obesity is known to predispose individuals to liver disease by increasing hepatic sensitivity to endotoxin. The aim of the present study was to determine the effect of mouse recombinant leptin on food intake, body weight, hepatic and plasma lipids and lipoproteins in alcohol-induced liver injury. METHOD Male Swiss mice weighing 28-32 g were administered ethanol (6.32 g x kg(-1) body weight, p.o.) for the first 30 days. Subsequently, ethanol-fed mice were given intraperitoneal injections of exogenous leptin (230 microg x kg(-1) body weight, i.p.) every alternate day for 15 days. At the end of the total experimental period of 45 days, plasma concentrations of total cholesterol, free fatty acids, triglycerides, lipoprotein lipase and lipoproteins were measured. RESULTS Exogenous leptin injections to alcohol-fed mice significantly (P<0.05) inhibited the rise in hepatic and plasma lipid and lipoprotein concentrations as compared with those of the unsupplemented ethanol fed mice. Food intake and average body weight at the end of the experimental period was significantly decreased on leptin administration. CONCLUSION Chronic administration of exogenous mouse recombinant leptin prevents the rise in lipids and lipoprotein concentrations significantly in an animal model of alcohol-induced hyperlipidemia.
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MESH Headings
- Administration, Oral
- Alcohol-Induced Disorders/blood
- Alcohol-Induced Disorders/drug therapy
- Animals
- Body Weight/drug effects
- Cholesterol/analysis
- Cholesterol, HDL/blood
- Cholesterol, HDL/drug effects
- Cholesterol, LDL/blood
- Cholesterol, LDL/drug effects
- Cholesterol, VLDL/blood
- Cholesterol, VLDL/drug effects
- Disease Models, Animal
- Eating/drug effects
- Ethanol/pharmacology
- Fatty Acids, Nonesterified/analysis
- Hyperlipidemias/chemically induced
- Hyperlipidemias/drug therapy
- Injections, Intraperitoneal
- Leptin/pharmacology
- Lipoprotein Lipase/blood
- Liver/chemistry
- Liver/drug effects
- Male
- Mice
- Triglycerides/analysis
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Affiliation(s)
- Vairappan Balasubramaniyan
- Department of Biochemistry, Faculty of Science, Annamalai University, 608 002, Tamil Nadu, Annamalainagar, India
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33
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Puchalski SS, Green JN, Rasmussen DD. Melatonin effect on rat body weight regulation in response to high-fat diet at middle age. Endocrine 2003; 21:163-7. [PMID: 12897381 DOI: 10.1385/endo:21:2:163] [Citation(s) in RCA: 60] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/10/2003] [Revised: 03/05/2003] [Accepted: 03/05/2003] [Indexed: 11/11/2022]
Abstract
We previously demonstrated that daily melatonin administration to middle-aged rats to restore youthful plasma melatonin levels also decreased body weight, visceral fat, plasma leptin, and plasma insulin to more youthful levels, without detectable changes in consumption of chow diet. We now evaluate: (a) whether melatonin alters consumption of a more precisely quantifiable liquid diet similar in high-fat content to the typical American diet; (b) differences between melatonin-induced endocrine responses in the fasted vs fed state; and (c) time course of these responses. Ten-month-old male Sprague- Dawley rats received liquid diet containing either 0.2 micro g/mL melatonin (MELATONIN) or vehicle (CONTROL) (n = 14/treatment); the diet was available throughout each night, but was removed for the final 10 h of each daytime. MELATONIN rats gained 4% body weight during the first 2 wk and then stabilized, whereas CONTROL rats continued to gain for an additional week, achieving 8% gain (p < 0.05 vs MELATONIN). During the first 3 wk, afternoon tail-blood leptin, but not insulin, levels decreased in melatonin-treated rats (p < 0.05 vs CONTROL). After 8 wk, half of the rats were killed at the midpoint of the dark period (NIGHT; fed) and half at the end of the light period (DAYTIME; fasted). NIGHT but not DAYTIME plasma leptin levels were decreased in MELATONIN rats, whereas DAYTIME but not NIGHT plasma insulin levels were decreased (p < 0.05 vs CONTROL). Melatonin treatment did not alter cumulative food consumption. Thus, melatonin decreased weight gain in response to high-fat diet, decreased plasma leptin levels within 3 wk-before decreasing plasma insulin-and exerted these metabolic effects independent of total food consumption.
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Affiliation(s)
- Stephaney S Puchalski
- VA Puget Sound Health Care System Mental Illness Research, Education and Clinical Center (MIRECC) and Department of Psychiatry, University of Washington, Seattle, WA 98108, USA.
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34
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Valle M, Gascón F, Martos R, Bermudo F, Ceballos P, Suanes A. Relationship between high plasma leptin concentrations and metabolic syndrome in obese pre-pubertal children. Int J Obes (Lond) 2003; 27:13-8. [PMID: 12532148 DOI: 10.1038/sj.ijo.0802154] [Citation(s) in RCA: 58] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
OBJECTIVE To evaluate the relationship between serum leptin levels and metabolic syndrome, fasting insulin level and anthropometric index in obese pre-pubertal children. DESIGN A cross-sectional study was carried out on obese children. SUBJECTS A study was made of 41 obese children (aged 6-9 y) and the same number of non-obese children (control group), matched by age and sex. METHODS Body mass index (BMI), waist/hip ratio (WHR) and blood pressure were determined in each child. Serum leptin, glucose, insulin, lipid profile, sex hormone binding globulin (SHBG), plasminogen activator inhibitor-1 (PAI-1), tissue-plasminogen activator (t-PA) and fibrinogen were all measured. RESULTS The serum leptin level was significantly higher in obese children (15.47 vs 4.73 ng/ml). In the obese group, leptin showed a positive correlation with BMI (P<0.001), insulin (P<0.001), triglycerides (P<0.05), PAI-1 (P<0.05) and t-PA (P<0.05), and correlated negatively with SHBG (P<0.01), apolipoprotein A-I (P<0.05) and high-density lipoproteins cholesterol (HDL-C) (P<0.05). Corrected for BMI and WHR, leptin (P partial=0.002) is only an independent predictive factor for basal insulin. Using multivariant regression analysis, only insulin (P partial=0.003) and BMI (P partial=0.018) were independent predictive factors for leptin. CONCLUSION For this age group, high leptin resistance may be another component of metabolic syndrome, and may be involved in its etiopathogenesis. The involvement of leptin in this syndrome may be indirect, modulating the insulin's action.
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Affiliation(s)
- M Valle
- Clinical Laboratory Department, Valle de los Pedroches Hospital, Pozoblanco, Córdoba, Spain.
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35
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Margetic S, Gazzola C, Pegg GG, Hill RA. Leptin: a review of its peripheral actions and interactions. Int J Obes (Lond) 2002; 26:1407-33. [PMID: 12439643 DOI: 10.1038/sj.ijo.0802142] [Citation(s) in RCA: 625] [Impact Index Per Article: 27.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/10/2001] [Revised: 04/02/2002] [Accepted: 05/27/2002] [Indexed: 12/11/2022]
Abstract
Following the discovery of leptin in 1994, the scientific and clinical communities have held great hope that manipulation of the leptin axis may lead to the successful treatment of obesity. This hope is not yet dashed; however the role of the leptin axis is now being shown to be ever more complex than was first envisaged. It is now well established that leptin interacts with pathways in the central nervous system and through direct peripheral mechanisms. In this review, we consider the tissues in which leptin is synthesized and the mechanisms which mediate leptin synthesis, the structure of leptin and the knowledge gained from cloning leptin genes in aiding our understanding of the role of leptin in the periphery. The discoveries of expression of leptin receptor isotypes in a wide range of tissues in the body have encouraged investigation of leptin interactions in the periphery. Many of these interactions appear to be direct, however many are also centrally mediated. Discovery of the relative importance of the centrally mediated and peripheral interactions of leptin under different physiological states and the variations between species is beginning to show the complexity of the leptin axis. Leptin appears to have a range of roles as a growth factor in a range of cell types: as be a mediator of energy expenditure; as a permissive factor for puberty; as a signal of metabolic status and modulation between the foetus and the maternal metabolism; and perhaps importantly in all of these interactions, to also interact with other hormonal mediators and regulators of energy status and metabolism such as insulin, glucagon, the insulin-like growth factors, growth hormone and glucocorticoids. Surely, more interactions are yet to be discovered. Leptin appears to act as an endocrine and a paracrine factor and perhaps also as an autocrine factor. Although the complexity of the leptin axis indicates that it is unlikely that effective treatments for obesity will be simply derived, our improving knowledge and understanding of these complex interactions may point the way to the underlying physiology which predisposes some individuals to apparently unregulated weight gain.
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Affiliation(s)
- S Margetic
- Central Queensland University, School of Chemical and Biomedical Sciences, Queensland, Australia
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36
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Ceddia RB, Koistinen HA, Zierath JR, Sweeney G. Analysis of paradoxical observations on the association between leptin and insulin resistance. FASEB J 2002; 16:1163-76. [PMID: 12153984 DOI: 10.1096/fj.02-0158rev] [Citation(s) in RCA: 189] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
Obesity is commonly associated with the development of insulin resistance and diabetes in humans and rodents. Insulin resistance and diabetes are observed in lipoatrophic individuals or rodent models of lipoatrophy. Here we focus on the role of leptin, the product of the obesity (ob) gene, in the development of insulin resistance and diabetes associated with obesity and lipoatrophy. We review the reported effects of leptin on whole body glucose metabolism and compare and contrast these with direct effects on skeletal muscle, fat and liver. This summary of paradoxical observations on the effects of leptin on glucose homeostasis and the ability of leptin to induce or improve insulin resistance suggests that a complex interplay exists between direct peripheral and centrally mediated effects of the hormone. Evidence suggesting that leptin acts as a mediator of insulin release from pancreatic beta cells is reviewed. Finally, intracellular signaling mechanisms stimulated by both leptin and insulin are discussed, with potential points of cross-talk suggested.
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Liu RH, Mizuta M, Kurose T, Matsukura S. Early events involved in the development of insulin resistance in Zucker fatty rat. Int J Obes (Lond) 2002; 26:318-26. [PMID: 11896486 DOI: 10.1038/sj.ijo.0801924] [Citation(s) in RCA: 38] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2001] [Revised: 07/10/2001] [Accepted: 10/16/2001] [Indexed: 11/08/2022]
Abstract
AIM To clarify the mechanism by which insulin resistance develops in obesity, Zucker fatty rats (ZFR) and lean litter mates (ZLR) were temporally subjected to oral glucose tolerance tests (OGTT) at 6 and 15 weeks of age. METHOD As candidates for causative factors of insulin resistance, plasma leptin, free fatty acids (FFA) and tumor necrosis factor (TNF)-alpha levels were evaluated. RESULTS There was no difference in the body weight between the two groups at 6 weeks of age, but ZFR were significantly heavier than ZLR at 15 weeks of age. At 6 weeks of age, blood glucose levels and area under the curve of glucose (AUCg) during OGTT were not significantly different between the two groups, while plasma insulin levels and area under the curve of insulin (AUCi) in the ZFR group were significantly higher than those in the ZLR group. At 15 weeks of age, the blood glucose levels and AUCg as well as plasma insulin levels and AUCi in the ZFR group during OGTT were significantly higher than those in the ZLR group. The ratio of fasting insulin to glucose in the ZFR group was significantly higher than that in the ZLR group at 6 and 15 weeks of age. Peripheral and portal plasma leptin and FFA levels were significantly higher in ZFR than ZLR both at 6 weeks and 15 weeks of age. Meanwhile, at 6 weeks, plasma TNF-alpha levels and expression of TNF-alpha protein in subcutaneous and visceral fat tissues were similar in both groups; however at 15 weeks, these were significantly higher in the ZFR group than the ZLR group. CONCLUSION These results suggest that FFA rather than TNF-alpha may play an important role in early events involved in the development of insulin resistance and TNF-alpha accelerates insulin resistance together with FFA in the later stage.
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Affiliation(s)
- R H Liu
- Third Department of Internal Medicine, Miyazaki Medical College. Miyazaki, Japan
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38
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Nogalska A, Swierczynski J. The age-related differences in obese and fatty acid synthase gene expression in white adipose tissue of rat. BIOCHIMICA ET BIOPHYSICA ACTA 2001; 1533:73-80. [PMID: 11514238 DOI: 10.1016/s1388-1981(01)00142-1] [Citation(s) in RCA: 19] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
To determine if the age-dependent increase of adiposity is directly related to altered obese (ob) and fatty acid synthase (FAS) gene expression, we assessed an adiposity index, leptin and FAS mRNA levels, FAS activity in perirenal adipose tissue and serum leptin concentration in rats aged 1, 2, 3, 6 and 20 months. The results indicate that there are two distinct phases of changes in perirenal white adipose tissue leptin mRNA level and serum leptin concentration. The first phase, between 1 and 3 months of the animals' lives, was characterized by a strong positive correlation between adiposity index and leptin mRNA level as well as serum leptin concentration. In the second phase (over 3 months) no significant changes of leptin mRNA and serum concentration occurred. A close correlation between the age-induced increase of leptin mRNA abundance and serum leptin concentration and the age-induced suppression of FAS gene expression in the same tissue was observed. This suggests that the changes of FAS gene expression occur in response to serum leptin concentration and that in mature rats the high level of ob gene expression and consequently the high leptin concentration protect the white adipose tissue cells against fat overload by two independent mechanisms: (a) preventing an increase of food intake through the leptin action on the hypothalamus; (b) inhibiting FAS gene expression and consequently decreasing the rate of lipogenesis.
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Affiliation(s)
- A Nogalska
- Department of Biochemistry, Medical University of Gdansk, ul. Debinki 1, 80-211, Gdansk, Poland
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39
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Chen XL, Lee K, Hartzell DL, Dean RG, Hausman GJ, McGraw RA, Della-Fera MA, Baile CA. Adipocyte insensitivity to insulin in growth hormone-transgenic mice. Biochem Biophys Res Commun 2001; 283:933-7. [PMID: 11350075 DOI: 10.1006/bbrc.2001.4882] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Growth hormone (GH) has an inhibitory effect on adipogenesis, and its effect is associated with insulin action in obesity. In this study, the relationship between GH effect on insulin sensitivity and adipocyte differentiation in vivo was investigated. Transgenic (TG) female mice expressing porcine GH had reduced body weights and weights of retroperitoneal and parametrial fat depots. Insulin treatment increased PPARgamma and GLUT4 expression in adipose tissue of WT mice but had no effect in TG mice. Content of transcription factors, PPARgamma and C/EBPalpha and beta, was higher in adipose tissue of WT mice, and for C/EBPalpha and PPARgamma, the difference occurred primarily in 24-, compared to 12-week-old, mice. Expression of preadipocyte factor-1 was higher in adipose tissue of TG mice, and expression of TNF-alpha and leptin was reduced in adipose tissue of 24-week-old TG mice. Our results suggest that increased expression of GH reduces adipogenesis by inducing adipocyte resistance to the adipogenic effect of insulin.
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Affiliation(s)
- X L Chen
- Diabetes Branch, NIDDK, National Institutes of Health, Bethesda, Maryland, USA
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40
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Saleh J, Blevins JE, Havel PJ, Barrett JA, Gietzen DW, Cianflone K. Acylation stimulating protein (ASP) acute effects on postprandial lipemia and food intake in rodents. Int J Obes (Lond) 2001; 25:705-13. [PMID: 11360154 DOI: 10.1038/sj.ijo.0801613] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/25/2000] [Revised: 11/30/2000] [Accepted: 01/05/2001] [Indexed: 11/08/2022]
Abstract
BACKGROUND In vitro studies have shown that acylation stimulating protein (ASP) stimulates triglyceride (TG) synthesis and storage in adipocytes. We have previously demonstrated that intraperitoneal (i.p.) injection of ASP in C57BL/6J mice accelerated TG clearance following an orally-administered fat load as well as reducing postprandial glucose levels. RESULTS In the present study, we first examined the effect of i.p. and intracerebroventricular (i.c.v.) injection of ASP on food intake in Sprague-Dawley rats. Intraperitoneal injection resulted in a short-term increase in food intake (maximum increase 29.3% within the first hour, P<0.025) decreasing thereafter as compared to vehicle alone. i.c.v. Administration of a comparable dose of ASP resulted in a similar but delayed increase in food intake with a maximum at 2-4 h, suggesting that the actions of ASP are peripherally mediated. However, there was no significant difference in 24 h food intake with either i.p. or i.c.v. injection. We also examined the effects of ASP on TG clearance in two obese mouse strains with different metabolic profiles: ob/ob (C57BL/6J-Lep(ob)) and db/db (C57BLKS/J-Lepr(db)). In a crossover design, the response to an oral fat load was determined with and without i.p. injection of exogenous ASP. In ob/ob mice, there was a 44% greater clearance of postprandial TG (area under the curve (AUC)=245+/-49 control vs 138+/-43 mg/dl h with ASP; P<0.05 by RM ANOVA). The db/db mice showed a greater response, with a 62% decrease in postprandial TG (AUC=4080+/-1489 control vs 1540+/-719 mg/dl h with ASP; P=0.004 by RM ANOVA). In addition there were decreases in postprandial glucose and non-esterified fatty acid (NEFA) levels in response to ASP. CONCLUSION These results are the first to report that ASP can increase food intake in rats and also enhance postprandial TG clearance in obese animals. These data therefore support previous in vitro evidence pointing to ASP as a regulator of lipid metabolism.
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Affiliation(s)
- J Saleh
- Mike Rosenbloom Laboratory for Cardiovascular Research, McGill University Health Centre, McGill University, Montreal, Quebec, Canada
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41
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Ceddia RB, William WN, Lima FB, Flandin P, Curi R, Giacobino JP. Leptin stimulates uncoupling protein-2 mRNA expression and Krebs cycle activity and inhibits lipid synthesis in isolated rat white adipocytes. EUROPEAN JOURNAL OF BIOCHEMISTRY 2000; 267:5952-8. [PMID: 10998055 DOI: 10.1046/j.1432-1327.2000.01664.x] [Citation(s) in RCA: 52] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
The treatment of rats and mice with leptin causes dramatic body fat reduction and in some cases even disappearance of fat tissue. Here, we report the effects of leptin (10 and 100 ng.mL-1) on isolated rat adipocytes maintained for 15 h in culture. Leptin decreased the incorporation of acetate into total lipids by 30%. A reduction in this incorporation (42%) was still observed after the leptin-cultivated adipocytes were exposed to a supra-physiological insulin concentration (10 000 microU.mL-1). On the other hand, leptin increased acetate degradation by 69% and the maximal activity of citrate synthase by 50% in isolated adipocytes. It also increased oleate degradation by 35 and 50% at concentrations of 10 and 100 ng. mL-1, respectively. Eventually, leptin upregulated the uncoupling protein-2 (UCP2) mRNA level by 63% and had no effect on uncoupling protein-3 (UCP3) mRNA in isolated adipocytes. The upregulation of UCP2 mRNA might have contributed to the stimulation of acetate and fatty acid degradation by leptin. The peripheral effects of leptin observed in this study are in line with the general energy dissipating role postulated for this hormone and for UCP2. They suggest mechanisms by which adipocytes regulate their fat content by an autocrine pathway without the participation of the central nervous system.
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Affiliation(s)
- R B Ceddia
- Department of Physical Education, Fluminense Federal University, Niterói, Rio de Janeiro, Brasil
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42
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Ruffin M, Nicolaidis S. Intracerebroventricular injection of murine leptin enhances the postprandial metabolic rate in the rat. Brain Res 2000; 874:30-6. [PMID: 10936221 DOI: 10.1016/s0006-8993(00)02570-1] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
Energy balance is achieved by means of a concomitant control of both food intake and energy expenditure. Leptin, synthesized in the adipose tissue, acts on brain structures and lowers body weight by inhibiting food intake and in parallel by enhancing energy expenditure i.e. metabolism or one of its components. Recording distinctly these components allowed us to assess the effect of an acute intracerebroventricular injection of leptin on both feeding pattern and background metabolism (i.e. energy expenditure free from the part of locomotor activity), respiratory quotient, feeding-related metabolism and locomotor activity-related metabolism. Leptin injection to Sprague-Dawley male rats induced an inhibition of feeding that began 90 min after the treatment and lasted 1 h before to return to the control feeding pattern level. Considering this late behavioral effect, it appeared that leptin may act during the postprandial period so that we recorded the different metabolic parameters following a 3 g calibrated meal itself preceded by leptin vs. artificial cerebrospinal fluid injection. Postprandial respiratory quotient was rapidly lowered in leptin-treated animals and subsequent background metabolism increased for 6 h. Thus it appeared that leptin increased the duration of the postprandial metabolic rate via the recruitment of endogenous fat stores. Enhancement in the thermic effect of food may be the reason for feeding behavior inhibition to be delayed.
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Affiliation(s)
- M Ruffin
- Institut Européen des Sciences du Goût et des Comportements Alimentaires (IESGCA), CNRS UPR 9054, Groupe Neurobiologie des Régulations, Collège de France.
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43
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Iritani N, Sugimoto T, Fukuda H. Gene expressions of leptin, insulin receptors and lipogenic enzymes are coordinately regulated by insulin and dietary fat in rats. J Nutr 2000; 130:1183-8. [PMID: 10801916 DOI: 10.1093/jn/130.5.1183] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
Abstract
Regulation of the gene expressions of leptin, insulin receptors and lipogenic enzymes was investigated after refeeding a fat-free diet or a 10 g/100 g corn oil diet to food-deprived rats. Plasma glucose and insulin concentrations began to increase 30 min after the feeding and further increased up until 8 h. In these rats, the expression of leptin mRNA in adipose tissue began to increase significantly only 30 min after feeding, and reached a maximum at 8-16 h. However, plasma leptin levels did not increase until 4 h after refeeding, then markedly increased and reached the maximal level after 8 h. The expression of leptin mRNA and plasma leptin concentrations generally were greater in rats fed the corn oil diet compared to those fed the fat-free diet. Insulin receptor mRNA concentrations in the liver and adipose tissue began to decrease 30 min after the refeeding, in contrast to the plasma insulin increase, and continued to decrease until 8 h. The expression of acetyl-CoA carboxylase and fatty acid synthase mRNA began to increase 4-8 h after feeding and reached maximal levels at 16-24 h. Leptin treatment suppressed the expression of lipogenic enzyme mRNA in rats fed the fat-free diet but not in corn oil-fed rats, in which the expression was suppressed by polyunsaturated fatty acids and leptin expression was higher. Thus, we suggest that the glucose and insulin-dependent expressions of leptin, insulin receptors and lipogenic enzymes are coordinately and/or mutually regulated by dietary manipulation.
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Affiliation(s)
- N Iritani
- Faculty of Human and Cultural Studies, Tezukayama Gakuin University, 4-2-2 Harumidai, Sakai, Osaka 590-0113, Japan
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44
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Takeuchi T, Tsutsumi O. Basal leptin concentrations in women with normal and dysfunctional ovarian conditions. Int J Gynaecol Obstet 2000; 69:127-33. [PMID: 10802080 DOI: 10.1016/s0020-7292(00)00178-8] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Abstract
OBJECTIVE To determine whether leptin is involved in ovarian function. METHODS Fasting serum samples were obtained from 20 women with normal menstrual cycles who were either obese or non-obese: 12 non-obese patients with polycystic ovary syndrome (PCOS), 8 obese patients with PCOS, 10 patients with stress-related hypothalamic amenorrhea, and 8 patients with weight loss-related hypothalamic amenorrhea. RESULTS Serum leptin levels were strongly related to body mass index (BMI) in each group, but there was no difference in the mean serum leptin levels among the BMI-matched study groups. A significant difference in the mean serum leptin levels was found between the non-obese and obese control groups (P<0.001) and between the non-obese and obese PCOS groups (P<0.001). CONCLUSIONS These findings indicate that circulating leptin levels in women with normal menstrual cycles and those with ovarian dysfunction are strongly related to BMI. Leptin does not appear to be primarily involved in regulating ovarian function.
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Affiliation(s)
- T Takeuchi
- Department of Obstetrics and Gynecology, Branch Hospital, Faculty of Medicine, University of Tokyo, Tokyo, Japan
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45
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Abstract
This paper reviews the general mechanisms by which leptin acts as a regulator of lipid reserves through changes in food intake, energy expenditure and fuel selection, with an emphasis on its direct effects on cellular lipid metabolism. Briefly, when leptin levels increase, food consumption decreases via modulation of hypothalamic neuropeptides. As well, normal decreases in energy expenditures (e.g. with diurnal cycles or reduced caloric intake) do not occur. This is probably caused by an increase in mitochondrial proton leak mediated by leptin via increases in sympathetic nervous system stimulation and thyroid hormone release. The decrease in caloric input coupled with relatively higher energy expenditure, therefore, leads to negative energy balance. Leptin also changes the fuel source from which ATP is generated. Fuel preference switches from carbohydrate (glucose) to lipid (fatty acids). This effect arises through stimulation of triacylglycerol catabolism by leptin. In vitro studies show that leptin is a potent stimulator of lipolysis and fatty acid oxidation in adipocytes and other cell types. Consequently, leptin is also a regulator of cellular triacylglycerol content. Hormonal regulation of leptin, as well as its role in fasting and seasonal weight gain and energy expenditure are also briefly discussed.
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Affiliation(s)
- S P Reidy
- Department of Biology, University of Ottawa, 30 Marie Curie, Ottawa, Ont., Canada
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46
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Zhang HH, Kumar S, Barnett AH, Eggo MC. Tumour necrosis factor-alpha exerts dual effects on human adipose leptin synthesis and release. Mol Cell Endocrinol 2000; 159:79-88. [PMID: 10687854 DOI: 10.1016/s0303-7207(99)00194-x] [Citation(s) in RCA: 70] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
The acute and chronic effects of tumour necrosis factor-alpha (TNF-alpha) on leptin production by human preadipocytes, differentiated preadipocytes, and mature adipocytes have been examined by competitive RT-PCR of leptin mRNA and by western blotting. In preadipocytes, secreted leptin was detectable after 5-day incubation in differentiation medium and this increased 4-fold by day 20. TNF-alpha blocked leptin synthesis during differentiation. In differentiated preadipocytes and mature adipocytes, TNF-alpha treatment resulted in time-dependent decreases in mRNA for leptin and glycerol-3-phosphate dehydrogenase (G3PD). In contrast, TNF-alpha (4-8-h treatment) resulted in a 4-fold increase in leptin release. This effect was lost at 24 h and leptin accumulation in culture medium was decreased 24-48 h after TNF-alpha addition. We conclude that TNF-alpha stimulates the release of preformed leptin from human mature adipocytes and existing differentiated preadipocytes, which may contribute to obesity/infection-linked hyperleptinemia, and that TNF-alpha inhibits leptin synthesis via inhibition of preadipocyte differentiation and induction of adipocyte dedifferentiation.
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Affiliation(s)
- H H Zhang
- Department of Medicine, University of Birmingham, UK
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47
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48
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Zimmet P, Boyko EJ, Collier GR, de Courten M. Etiology of the metabolic syndrome: potential role of insulin resistance, leptin resistance, and other players. Ann N Y Acad Sci 1999; 892:25-44. [PMID: 10842650 DOI: 10.1111/j.1749-6632.1999.tb07783.x] [Citation(s) in RCA: 145] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
Obesity and Type 2 diabetes are now major public health issues in developed nations and have reached epidemic proportions in many developing nations, as well as disadvantaged groups in developed countries, e.g., Mexican-Americans, African-Americans, and Australian Aborigines. These groups all show hyperinsulinemia and insulin resistance, which have been demonstrated to be future predictors of Type 2 diabetes and have also been suggested as key factors in the etiology of the Metabolic Syndrome. It is now increasingly recognized that Type 2 diabetes is part of a cluster of cardiovascular disease (CVD) risk factors comprising the Metabolic Syndrome. This group is at very high risk of atherosclerosis because each of the risk factors in the Metabolic Syndrome cluster in its own right is an important CVD risk factor. They also contribute cumulatively to atherosclerosis. A key strategy in reducing macrovascular disease lies in the better understanding of the Metabolic Syndrome--glucose intolerance, hypertension, hyperlipidemia, and central obesity. Although it has been suggested that hyperinsulinemia/insulin resistance is the central etiological factor for the Metabolic Syndrome, epidemiological data do not support the idea that this can account for all of the cluster abnormalities. We have animal and human data suggesting that hyperleptinemia rather than, or synergistically with, hyperinsulinemia may play a central role in the genesis of the CVD risk factor cluster that constitutes the syndrome. Studies in Psammomys obesus (the Israeli sand rat) suggest hyperinsulinemia/insulin resistance is an early metabolic lesion in the development of obesity and Type 2 diabetes. This animal also develops other features of the Metabolic Syndrome, making it an excellent model to investigate etiology. Psammomys, when placed on an ad libitum laboratory diet, develops hyperinsulinemia, insulin resistance, impaired glucose tolerance, diabetes, and dyslipidemia. It also develops hyperleptinemia and leptin insensitivity, and hyperleptinemia is correlated with insulin resistance independent of changes in body weight. It is likely that a similar sequence occurs in the transition from the prediabetic state to Type 2 diabetes in humans. More recently, other potential players in the etiology of the Metabolic Syndrome have been suggested including endothelial dysfunction and acetylation-stimulating protein (ASP). It has been suggested that endothelial dysfunction may be an antecedent for both Type 2 diabetes and the Metabolic Syndrome. In addition, ASP is a serious new candidate for an important role in insulin resistance. The ASP pathway plays a critical role in fatty acid metabolism and storage, and it has been suggested that ineffective storage of fatty acids by adipocytes due to a defect in the ASP pathway may lead to insulin resistance and Type 2 diabetes.
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Affiliation(s)
- P Zimmet
- International Diabetes Institute, Melbourne, Australia.
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Leong KS, Wilding JP. Obesity and diabetes. BAILLIERE'S BEST PRACTICE & RESEARCH. CLINICAL ENDOCRINOLOGY & METABOLISM 1999; 13:221-37. [PMID: 10761864 DOI: 10.1053/beem.1999.0017] [Citation(s) in RCA: 41] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
Obesity, particularly truncal obesity, is closely correlated to the prevalence of diabetes and cardiovascular disease. Plasma leptin, tumour necrosis factor-alpha and non-esterified fatty acid levels are all elevated in obesity and play a role in causing insulin resistance. Diabetic glycaemic control and insulin resistance improve with reductions in obesity, but the treatment of obesity is difficult, and sustained weight reduction rarely occurs with dietary management alone. Hypocaloric diets should be combined with education and low-impact exercise, as well as behavioural techniques used to encourage long-term changes. Weight-reducing drugs have a role in the management of obesity but only as part of such a total package. Newer anti-obesity drugs such as orlistat and sibutramine are well tolerated and have been shown to improve glycaemic control in diabetes. It is probable that drugs developed in the future will act at different sites in the pathways regulating body weight, but they may have to be used in combination.
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Affiliation(s)
- K S Leong
- University Clinical Department, University Hospital Aintree, Liverpool, UK
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Gustafson TA, Moodie SA, Lavan BE. The insulin receptor and metabolic signaling. Rev Physiol Biochem Pharmacol 1999; 137:71-190. [PMID: 10207305 DOI: 10.1007/3-540-65362-7_5] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
Affiliation(s)
- T A Gustafson
- Metabolex, Inc., Section of Signal Transduction, Hayward, CA 94545, USA
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