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Tokdemir M, Erbak E, Tunçez FT, Elmali F, Yilmaz HE. Evaluation of leptin, insulin, orexin, neuropeptide y (NPY) levels in postmortem CSF samples in suicide deaths. J Affect Disord 2025; 381:303-309. [PMID: 40187429 DOI: 10.1016/j.jad.2025.04.015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/25/2024] [Revised: 03/28/2025] [Accepted: 04/02/2025] [Indexed: 04/07/2025]
Abstract
BACKGROUND Suicide remains a significant global public health issue. According to the World Health Organization (WHO), suicide was the third leading cause of mortality among individuals aged 15-29 in 2021, with a total of approximately 726,000 cases reported annually. The etiology of suicide is complex, involving a combination of biological, genetic, and environmental factors, as well as family history, gender, age, personality traits, cultural background, geographic location, medical conditions, mental illnesses, addictions, and psychosocial stressors. Dysregulation of the Hypothalamic Pituitary Adrenal (HPA) axis and the effects of chronic stress play significant roles in the pathophysiology of mood disorders and suicidal behavior. OBJECTIVE This study aimed to investigate the levels of Neuropeptide Y (NPY), Orexin, Leptin, and Insulin in cerebrospinal fluid (CSF) samples of individuals who died by suicide compared to those who died from non-suicidal causes. METHOD The study examined 35 cases of suicide by hanging and 35 cases of non-suicidal deaths unrelated to head trauma. Levels of NPY, Orexin, Leptin, and Insulin in CSF samples collected during toxicological examinations were compared between suicide and control groups. RESULTS NPY levels were significantly higher in the suicide group than in the control group (p < 0.001). No statistically significant differences were found in Orexin (p = 0.194), Insulin (p = 0.892), or Leptin (p = 0.445) levels between the groups. CONCLUSIONS While no definitive biomarkers for diagnosing or predicting suicidal behavior exist, this panel of biomarkers could provide valuable insights for developing targeted treatments to manage patients at risk.
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Affiliation(s)
- Mehmet Tokdemir
- Izmir Katip Celebi University School of Medicine, Department of Forensic Medicine, Izmir, Turkey; Council of Forensic Medicine Chairmanship of Group, Izmir, Turkey.
| | - Esra Erbak
- Izmir Katip Celebi University School of Medicine, Department of Forensic Medicine, Izmir, Turkey
| | - Ferhat Turgut Tunçez
- Izmir Katip Celebi University School of Medicine, Department of Forensic Medicine, Izmir, Turkey
| | - Ferhan Elmali
- Izmir Katip Celebi University School of Medicine, Department of Biostatistics, Izmir, Turkey
| | - Huriye Erbak Yilmaz
- Izmir Katip Celebi University School of Medicine, Department of Biochemistry, Izmir, Turkey; Izmir Biomedicine and Genome Center, Izmir, Turkey
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Stefanakis K, Upadhyay J, Ramirez-Cisneros A, Patel N, Sahai A, Mantzoros CS. Leptin physiology and pathophysiology in energy homeostasis, immune function, neuroendocrine regulation and bone health. Metabolism 2024; 161:156056. [PMID: 39481533 DOI: 10.1016/j.metabol.2024.156056] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/04/2024] [Revised: 10/28/2024] [Accepted: 10/28/2024] [Indexed: 11/02/2024]
Abstract
Since its discovery and over the past thirty years, extensive research has significantly expanded our understanding of leptin and its diverse roles in human physiology, pathophysiology and therapeutics. A prototypical adipokine initially identified for its critical function in appetite regulation and energy homeostasis, leptin has been revealed to also exert profound effects on the hypothalamic-pituitary-gonadal, thyroid, adrenal and growth hormone axis, differentially between animals and humans, as well as in regulating immune function. Beyond these roles, leptin plays a pivotal role in significantly affecting bone health by promoting bone formation and regulating bone metabolism both directly and indirectly through its neuroendocrine actions. The diverse actions of leptin are particularly notable in leptin-deficient animal models and in conditions characterized by low circulating leptin levels, such as lipodystrophies and relative energy deficiency. Conversely, the effectiveness of leptin is attenuated in leptin-sufficient states, such as obesity and other high-adiposity conditions associated with hyperleptinemia and leptin tolerance. This review attempts to consolidate 30 years of leptin research with an emphasis on its physiology and pathophysiology in humans, including its promising therapeutic potential. We discuss preclinical and human studies describing the pathophysiology of energy deficiency across organ systems and the significant role of leptin in regulating neuroendocrine, immune, reproductive and bone health. We finally present past proof of concept clinical trials of leptin administration in leptin-deficient subjects that have demonstrated positive neuroendocrine, reproductive, and bone health outcomes, setting the stage for future phase IIb and III randomized clinical trials in these conditions.
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Affiliation(s)
- Konstantinos Stefanakis
- Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
| | - Jagriti Upadhyay
- Department of Medicine, Lahey Hospital and Medical Center, Burlington, MA, USA
| | - Arantxa Ramirez-Cisneros
- Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
| | - Nihar Patel
- Department of Medicine, Lahey Hospital and Medical Center, Burlington, MA, USA
| | - Akshat Sahai
- Vassar Brothers Medical Center, Poughkeepsie, NY, USA
| | - Christos S Mantzoros
- Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA; Department of Medicine, Boston VA Healthcare System, Boston, MA, USA.
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Stefanakis K, Samiotaki M, Papaevangelou V, Valenzuela-Vallejo L, Giannoukakis N, Mantzoros CS. Longitudinal proteomics of leptin treatment in humans with acute and chronic energy deficiency-induced hypoleptinemia reveal novel, mainly immune-related, pleiotropic effects. Metabolism 2024; 159:155984. [PMID: 39097160 DOI: 10.1016/j.metabol.2024.155984] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/02/2024] [Revised: 07/26/2024] [Accepted: 07/29/2024] [Indexed: 08/05/2024]
Abstract
BACKGROUND Leptin is known for its metabolic, immunomodulatory and neuroendocrine properties, but the full spectrum of molecules downstream of leptin and relevant underlying mechanisms remain to be fully clarified. Our objective was to identify proteins and pathways influenced by leptin through untargeted proteomics in two clinical trials involving leptin administration in lean individuals. METHODS We performed untargeted liquid chromatography-tandem mass spectrometry serum proteomics across two studies a) Short-term randomized controlled crossover study of lean male and female humans undergoing a 72-h fast with concurrent administration of either placebo or high-dose leptin; b) Long-term (36-week) randomized controlled trial of leptin replacement therapy in human females with acquired relative energy deficiency and hypoleptinemia. We explored longitudinal proteomic changes and run adjusted mixed models followed by post-hoc tests. We further attempted to identify ontological pathways modulated during each experimental condition and/or comparison, through integrated qualitative pathway and enrichment analyses. We also explored dynamic longitudinal relationships between the circulating proteome with clinical and hormonal outcomes. RESULTS 289 and 357 unique proteins were identified per each respective study. Short-term leptin administration during fasting markedly upregulated several proinflammatory molecules, notably C-reactive protein (CRP) and cluster of differentiation (CD) 14, and downregulated lecithin cholesterol acyltransferase and several immunoglobulin variable chains, in contrast with placebo, which produced minimal changes. Quantitative pathway enrichment further indicated an upregulation of the acute phase response and downregulation of immunoglobulin- and B cell-mediated immunity by leptin. These changes were independent of participants' biological sex. In the long term study, leptin likewise robustly and persistently upregulated proteins of the acute phase response, and downregulated immunoglobulin-mediated immunity. Leptin also significantly and differentially affected a wide array of proteins related to immune function, defense response, coagulation, and inflammation compared with placebo. These changes were more notable at the 24-week visit, coinciding with the highest measured levels of serum leptin. We further identified distinct co-regulated clusters of proteins and clinical features during leptin administration indicating robust longitudinal correlations between the regulation of immunoglobulins, immune-related molecules, serpins (including cortisol and thyroxine-binding globulins), lipid transport molecules and growth factors, in contrast with placebo, which did not produce similar associations. CONCLUSIONS These high-throughput longitudinal results provide unique functional insights into leptin physiology, and pave the way for affinity-based proteomic analyses measuring several thousands of molecules, that will confirm these data and may fully delineate underlying mechanisms.
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Affiliation(s)
- Konstantinos Stefanakis
- Department of Internal Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
| | - Martina Samiotaki
- Institute for Bioinnovation, Biomedical Sciences Research Center "Alexander Fleming", Fleming 34, 166 72 Vari, Greece
| | - Vassiliki Papaevangelou
- Third Department of Paediatrics, Attikon University Hospital, National and Kapodistrian University of Athens, Greece
| | - Laura Valenzuela-Vallejo
- Department of Internal Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA
| | - Nick Giannoukakis
- Department of Pathology, University of Pittsburgh, Pittsburgh, PA, United States
| | - Christos S Mantzoros
- Department of Internal Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA
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Karimi R, Yanovich A, Elbarbry F, Cleven A. Adaptive Effects of Endocrine Hormones on Metabolism of Macronutrients during Fasting and Starvation: A Scoping Review. Metabolites 2024; 14:336. [PMID: 38921471 PMCID: PMC11205672 DOI: 10.3390/metabo14060336] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2024] [Revised: 06/08/2024] [Accepted: 06/12/2024] [Indexed: 06/27/2024] Open
Abstract
Food deprivation can occur for different reasons. Fasting (<24 h duration) occurs to meet religious or well-being goals. Starvation (>1-day duration) occurs when there is intentional (hunger strike or treatment of a medical condition) or unintentional (anorexia nervosa, drought, epidemic famine, war, or natural disaster) food deprivation. A scoping review was undertaken using the PubMed database to explore 1805 abstracts and review 88 eligible full-text articles to explore the adaptive relationships that emerge between cortisol, insulin, glucagon, and thyroid hormones on the metabolic pathways of macronutrients in humans during fasting and starvation. The collected data indicate that fasting and starvation prime the human body to increase cortisol levels and decrease the insulin/glucagon ratio and triiodothyronine (T3) levels. During fasting, increased levels of cortisol and a decreased insulin/glucagon ratio enhance glycogenolysis and reduce the peripheral uptake of glucose and glycogenesis, whereas decreased T3 levels potentially reduce glycogenolysis. During starvation, increased levels of cortisol and a decreased insulin/glucagon ratio enhance lipolysis, proteolysis, fatty acid and amino acid oxidation, ketogenesis, and ureagenesis, and decreased T3 levels reduce thermogenesis. We present a potential crosstalk between T3 and the above hormones, including between T3 and leptin, to extend their adaptive roles in the metabolism of endogenous macronutrients during food deprivation.
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Affiliation(s)
- Reza Karimi
- Pacific University School of Pharmacy, 222 SE 8th Avenue, HPC-Ste 451, Hillsboro, OR 97123, USA; (A.Y.); (F.E.); (A.C.)
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Perez-Leighton C, Kerr B, Scherer PE, Baudrand R, Cortés V. The interplay between leptin, glucocorticoids, and GLP1 regulates food intake and feeding behaviour. Biol Rev Camb Philos Soc 2024; 99:653-674. [PMID: 38072002 DOI: 10.1111/brv.13039] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2023] [Revised: 11/21/2023] [Accepted: 12/01/2023] [Indexed: 05/09/2024]
Abstract
Nutritional, endocrine, and neurological signals converge in multiple brain centres to control feeding behaviour and food intake as part of the allostatic regulation of energy balance. Among the several neuroendocrine systems involved, the leptin, glucocorticoid, and glucagon-like peptide 1 (GLP1) systems have been extensively researched. Leptin is at the top hierarchical level since its complete absence is sufficient to trigger severe hyperphagia. Glucocorticoids are key regulators of the energy balance adaptation to stress and their sustained excess leads to excessive adiposity and metabolic perturbations. GLP1 participates in metabolic adaptation to food intake, regulating insulin secretion and satiety by parallel central and peripheral signalling systems. Herein, we review the brain and peripheral targets of these three hormone systems that integrate to regulate food intake, feeding behaviour, and metabolic homeostasis. We examine the functional relationships between leptin, glucocorticoids, and GLP1 at the central and peripheral levels, including the cross-regulation of their circulating levels and their cooperative or antagonistic actions at different brain centres. The pathophysiological roles of these neuroendocrine systems in dysregulated intake are explored in the two extremes of body adiposity - obesity and lipodystrophy - and eating behaviour disorders.
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Affiliation(s)
- Claudio Perez-Leighton
- Departmento de Fisiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Av. Libertador Bernardo O'Higgins 340, Santiago, 830024, Chile
| | - Bredford Kerr
- Centro de Biología Celular y Biomedicina-CEBICEM, Facultad de Medicina y Ciencia, Universidad San Sebastián, Carmen Sylva 2444, Providencia, Santiago, Chile
| | - Philipp E Scherer
- Touchstone Diabetes Center, The University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX, 75390, USA
| | - René Baudrand
- Departmento de Endocrinología, Facultad de Medicina, Pontificia Universidad Católica de Chile, Av. Libertador Bernardo O'Higgins 340, Santiago, 830024, Chile
- Centro Translacional de Endocrinología (CETREN), Facultad de Medicina, Pontificia Universidad Católica de Chile, Av. Libertador Bernardo O'Higgins 340, Santiago, 830024, Chile
| | - Víctor Cortés
- Departmento de Nutrición, Diabetes y Metabolismo, Facultad de Medicina, Pontificia Universidad Católica de Chile, Av. Libertador Bernardo O'Higgins 340, Santiago, 830024, Chile
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Kokkorakis M, Katsarou A, Katsiki N, Mantzoros CS. Milestones in the journey towards addressing obesity; Past trials and triumphs, recent breakthroughs, and an exciting future in the era of emerging effective medical therapies and integration of effective medical therapies with metabolic surgery. Metabolism 2023; 148:155689. [PMID: 37689110 DOI: 10.1016/j.metabol.2023.155689] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2023] [Revised: 08/28/2023] [Accepted: 08/28/2023] [Indexed: 09/11/2023]
Abstract
The 21st century is characterized by an increasing incidence and prevalence of obesity and the burden of its associated comorbidities, especially cardiometabolic diseases, which are reaching pandemic proportions. In the late '90s, the "black box" of adipose tissue and energy homeostasis was opened with the discovery of leptin, transforming the adipose tissue from an "inert fat-storage organ" to the largest human endocrine organ and creating the basis on which more intensified research efforts to elucidate the pathogenesis of obesity and develop novel treatments were based upon. Even though leptin was eventually not proven to be the "standalone magic bullet" for the treatment of common/polygenic obesity, it has been successful in the treatment of monogenic obesity syndromes. Additionally, it shifted the paradigm of treating obesity from a condition due to "lack of willpower" to a disease due to distinct underlying biological mechanisms for which specific pharmacotherapies would be needed in addition to lifestyle modification. Subsequently, the melanocortin pathway proved to be an equally valuable pathway for the pharmacotherapy of obesity. Melanocortin receptor agonists have recently been approved for treating certain types of syndromic obesity. Other molecules- such as incretins, implicated in energy and glucose homeostasis- are secreted by the gastrointestinal tract. Glucagon-like peptide 1 (GLP-1) is the most prominent one, with GLP-1 analogs approved for common/polygenic obesity. Unimolecular combinations with other incretins, e.g., GLP-1 with gastric inhibitory polypeptide and/or glucagon, are expected to be approved soon as more effective pharmacotherapies for obesity and its comorbidities. Unimolecular combinations with other compounds and small molecules activating the receptors of these molecules are currently under investigation as promising future pharmacotherapies. Moreover, metabolic and bariatric surgery has also demonstrated impressive results, especially in the case of morbid obesity. Consequently, this broadening therapeutic armamentarium calls for a well-thought-after and well-coordinated multidisciplinary approach, for instance, through cardiometabolic expertise centers, that would ideally address effectively and cost-effectively obesity and its comorbidities, providing tangible benefits to large segments of the population.
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Affiliation(s)
- Michail Kokkorakis
- Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA
| | - Angeliki Katsarou
- Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA
| | - Niki Katsiki
- Department of Nutritional Sciences and Dietetics, International Hellenic University, 57400 Thessaloniki, Greece
| | - Christos S Mantzoros
- Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; Section of Endocrinology, VA Boston Healthcare System, Harvard Medical School, Boston, MA 02115, USA.
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Xiong LI, Garfinkel A. Are physiological oscillations physiological? J Physiol 2023. [PMID: 37622389 DOI: 10.1113/jp285015] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2023] [Accepted: 08/03/2023] [Indexed: 08/26/2023] Open
Abstract
Despite widespread and striking examples of physiological oscillations, their functional role is often unclear. Even glycolysis, the paradigm example of oscillatory biochemistry, has seen questions about its oscillatory function. Here, we take a systems approach to argue that oscillations play critical physiological roles, such as enabling systems to avoid desensitization, to avoid chronically high and therefore toxic levels of chemicals, and to become more resistant to noise. Oscillation also enables complex physiological systems to reconcile incompatible conditions such as oxidation and reduction, by cycling between them, and to synchronize the oscillations of many small units into one large effect. In pancreatic β-cells, glycolytic oscillations synchronize with calcium and mitochondrial oscillations to drive pulsatile insulin release, critical for liver regulation of glucose. In addition, oscillation can keep biological time, essential for embryonic development in promoting cell diversity and pattern formation. The functional importance of oscillatory processes requires a re-thinking of the traditional doctrine of homeostasis, holding that physiological quantities are maintained at constant equilibrium values, a view that has largely failed in the clinic. A more dynamic approach will initiate a paradigm shift in our view of health and disease. A deeper look into the mechanisms that create, sustain and abolish oscillatory processes requires the language of nonlinear dynamics, well beyond the linearization techniques of equilibrium control theory. Nonlinear dynamics enables us to identify oscillatory ('pacemaking') mechanisms at the cellular, tissue and system levels.
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Affiliation(s)
- Lingyun Ivy Xiong
- Department of Stem Cell Biology and Regenerative Medicine, Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, Keck School of Medicine of the University of Southern California, Los Angeles, CA, USA
- Department of Quantitative and Computational Biology, University of Southern California, Los Angeles, CA, USA
| | - Alan Garfinkel
- Departments of Medicine (Cardiology) and Integrative Biology and Physiology, University of California, Los Angeles, CA, USA
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Luo G, Li Y, Yao C, Li M, Li J, Zhang X. Prevalence of overweight and obesity in patients with major depressive disorder with anxiety: Mediating role of thyroid hormones and metabolic parameters. J Affect Disord 2023; 335:298-304. [PMID: 37201896 DOI: 10.1016/j.jad.2023.05.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/21/2023] [Revised: 04/28/2023] [Accepted: 05/05/2023] [Indexed: 05/20/2023]
Abstract
BACKGROUNDS Anxiety is a common comorbidity in major depressive disorder (MDD); however, its role in overweight and obesity in MDD patients remains unclear. We examined the relationship between severe anxiety and overweight and obesity, as well as the mediating role of thyroid hormones and metabolic parameters in MDD patients. METHODS This cross-sectional study recruited 1718 first-episode drug-naïve MDD outpatients. All participants were rated on the Hamilton Depression Rating Scale for depression and Hamilton Anxiety Rating Scale for anxiety and measured in thyroid hormones and metabolic parameters. RESULTS A total of 218 (12.7 %) individuals had severe anxiety. The prevalence of overweight and obesity in patients with severe anxiety was 62.8 % and 5.5 %, respectively. Severe anxiety symptoms were associated with overweight (Odds Ratio [OR]: 1.47, 95 % CI: 1.08, 2.00) and obesity (OR: 2.10, 95 % CI: 1.07, 4.15). The association between severe anxiety and overweight was mainly attenuated by thyroid hormones (40.4 %), blood pressure (31.9 %), and plasma glucose (19.1 %). For obesity, the association with severe anxiety was mainly attenuated by thyroid hormones (48.2 %), blood pressure (39.1 %), and total cholesterol (28.2 %). LIMITATIONS Due to the cross-sectional design, no causal relationship could be derived. CONCLUSIONS Thyroid hormones and metabolic parameters can explain the risk of overweight and obesity associated with severe anxiety in MDD patients. These findings add to the knowledge of the pathological pathway of overweight and obesity in MDD patients with comorbid severe anxiety.
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Affiliation(s)
- Guoshuai Luo
- Laboratory of Biological Psychiatry, Institute of Mental Health, Tianjin Anding Hospital, Mental Health Center of Tianjin Medical University, Tianjin, China, 300222
| | - Yaxi Li
- Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, 3210 Humin Rd, Shanghai 201108, China
| | - Cong Yao
- Laboratory of Biological Psychiatry, Institute of Mental Health, Tianjin Anding Hospital, Mental Health Center of Tianjin Medical University, Tianjin, China, 300222
| | - Meijuan Li
- Laboratory of Biological Psychiatry, Institute of Mental Health, Tianjin Anding Hospital, Mental Health Center of Tianjin Medical University, Tianjin, China, 300222
| | - Jie Li
- Laboratory of Biological Psychiatry, Institute of Mental Health, Tianjin Anding Hospital, Mental Health Center of Tianjin Medical University, Tianjin, China, 300222.
| | - Xiangyang Zhang
- Key Laboratory of Mental Health, Institute of Psychology, Chinese Academy of Sciences, Beijing 100101, China.
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Reddy R, Guo Y, Raju V, Faghih RT. Characterization of Leptin Secretion in Premenopausal Obese Women Treated with Bromocriptine. ANNUAL INTERNATIONAL CONFERENCE OF THE IEEE ENGINEERING IN MEDICINE AND BIOLOGY SOCIETY. IEEE ENGINEERING IN MEDICINE AND BIOLOGY SOCIETY. ANNUAL INTERNATIONAL CONFERENCE 2023; 2023:1-6. [PMID: 38082631 DOI: 10.1109/embc40787.2023.10340951] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/18/2023]
Abstract
Leptin, a hormone secreted by adipose tissue, is primarily responsible for inhibiting hunger and maintaining energy balance. Improper leptin secretion may result in hyperleptinemia (excess secretion of leptin) or leptin resistance, both of which contribute to obesity. Diagnosing abnormal leptin secretion may help treat this underlying cause of obesity. Therefore, continuous monitoring of the level of leptin may help characterize its secretion dynamics and also help devise an appropriate treatment. In this research, we consider leptin hormone concentration data taken over a 24 hour time period from eighteen healthy premenopausal obese women before and after treatment with a dopamine agonist, bromocriptine, and deconvolve the observed leptin hormone levels to estimate the number, timing, and magnitude of the underlying leptin secretory pulses. We find that there is an overall decrease in leptin secretion, particularly during sleep, but the changes in the secretory and clearance rates, and the number of pulses underlying the secretion process are not statistically significant.Clinical relevance- This work seeks to understand the effect of bromocriptine on leptin secretory dynamics and will help further current understanding of the effect of bromocriptine in relation to obesity.
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Kawasaki Y, Kitamura E, Kasai T. Impact of Body Composition on Sleep and Its Relationship with Sleep Disorders: Current Insights. Nat Sci Sleep 2023; 15:375-388. [PMID: 37220427 PMCID: PMC10200107 DOI: 10.2147/nss.s340946] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/29/2022] [Accepted: 05/04/2023] [Indexed: 05/25/2023] Open
Abstract
Sleep is involved in many physiological processes and is essential for both physical and mental health. Obesity and sleep deprivation due to sleep disorders are major public health issues. Their incidence is increasing, and they have a wide range of adverse health-related consequences, including life-threatening cardiovascular disease. The impact of sleep on obesity and body composition is well-known, and many studies have shown an association between insufficient or excessive sleep duration and obesity, body fat percentage, and weight gain. However, there is growing evidence of the effects of body composition on sleep and sleep disorders (particularly sleep disordered breathing) through anatomical and physiological mechanisms (nocturnal fluid shift, core body temperature, or diet). Although some research has been conducted on the bidirectional effects of sleep-disordered breathing and body composition, the specific effects of obesity and body composition on sleep and the underlying mechanisms that explain these effects remain unclear. Therefore, this review summarizes the findings on the effects of body composition on sleep and draws conclusions and proposals for future research in this field.
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Affiliation(s)
- Yu Kawasaki
- Department of Obstetrics and Gynecology, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Eri Kitamura
- Department of Obstetrics and Gynecology, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Takatoshi Kasai
- Department of Cardiovascular Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan
- Sleep and Sleep-Disordered Breathing Center, Juntendo University Hospital, Tokyo, Japan
- Cardiovascular Respiratory Sleep Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan
- Department of Cardiovascular Management and Remote Monitoring, Juntendo University Graduate School of Medicine, Tokyo, Japan
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Orlova E, Loginova O, Shirshev S. Leptin regulates thymic plasmacytoid dendritic cell ability to influence the thymocyte distribution in vitro. Int Immunopharmacol 2023; 117:109912. [PMID: 36857934 DOI: 10.1016/j.intimp.2023.109912] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2022] [Revised: 02/07/2023] [Accepted: 02/14/2023] [Indexed: 03/03/2023]
Abstract
Leptin, the adipocyte-derived hormone, involved in regulating food intake and body weight, plays an important role in immunity and reproduction. Leptin signals via the specific membrane receptors expressed in most types of immune cells including dendritic cells (DCs) and thymocytes. Leptin enhances thymopoiesis and modulates T-cell-mediated immunity. Thymic plasmacytoid DCs (pDCs) are predominated in the thymus. They play an important role in thymocyte differentiation. We have analyzed whether leptin mediates its effects on human thymocytes by influencing on pDCs. We used leptin at concentration corresponding to its level during II-III trimesters of physiological pregnancy. We cultivated leptin-primed pDCs with autologous thymocytes and estimated the main thymocyte subsets expressing αβ chains of the T-cell receptor (αβTCR), natural regulatory T-cells (tTreg), natural T-helpers producing interleukin-17 (nTh17) and invariant natural killer T-cells (iNKT) in vitro. We have shown that leptin augmented CD86, CD276 expressions and depressed IL-10 productions by pDCs. Leptin-primed pDCs decreased the percentage of CD4+CD8+αβTCR+ thymocytes, increased CD4hiCD8-/loαβTCR+ cells. pDCs cultivated with leptin decreased the number of iNKT precursors, and did not change the number of tTreg and nTh17 precursors. Thus, leptin's important role in regulation of thymic pDC abilities to influence on the thymocyte distribution was indicated in vitro.
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Affiliation(s)
- Ekaterina Orlova
- Laboratory of Immunoregulation, Perm Federal Research Center, Ural Branch of the Russian Academy of Sciences, 13A Lenina str., 614015 Perm, Russia.
| | - Olga Loginova
- Laboratory of Immunoregulation, Perm Federal Research Center, Ural Branch of the Russian Academy of Sciences, 13A Lenina str., 614015 Perm, Russia.
| | - Sergei Shirshev
- Laboratory of Immunoregulation, Perm Federal Research Center, Ural Branch of the Russian Academy of Sciences, 13A Lenina str., 614015 Perm, Russia.
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Harris RBS. Sucrose solution, but not liquid sucrose diet, leads to leptin resistance irrespective of the time of day that sucrose is available. Physiol Behav 2023; 258:114002. [PMID: 36273496 PMCID: PMC11352078 DOI: 10.1016/j.physbeh.2022.114002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2022] [Revised: 10/11/2022] [Accepted: 10/18/2022] [Indexed: 11/29/2022]
Abstract
Rats offered free access to sucrose solution in addition to a sucrose-free composite diet develop leptin resistance whereas those consuming a similar amount of sucrose from a dry diet remain leptin responsive. Here we tested whether rats consuming a complete high sucrose diet in liquid form also became leptin resistant. Female Sprague Dawley rats were offered a sucrose free diet (NS), a dry high sucrose diet (HS), NS diet plus 30% sucrose solution (LiqS), NS diet in liquid form (NSLiq) or HS diet in Liquid form (HSLiq). After 30 days LiqS rats were leptin resistant, but all other groups were leptin responsive even though HSLiq rats consumed as much sucrose as LiqS rats and NSLiq rats had the greatest amount of body fat. Therefore, development of leptin resistance is dependent upon the consumption of sucrose independent of any other nutrients. Because LiqS rats consume sucrose throughout the day and night we tested whether limiting sucrose solution access to either the light or dark period prevented development of leptin resistance. Leptin resistant LiqS rats were either given free access to sucrose, had access to sucrose only at night or had access only during the day. The intake of rats with limited access was supplemented to the level of those with free access by tube-feeding. The results of this study show that leptin resistance of LiqS rats is independent of when the sucrose is consumed and is unrelated to total energy intake, body fat mass or serum leptin concentration.
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Affiliation(s)
- Ruth B S Harris
- Department of Physiology, Medical College of Georgia at Augusta University, Natural Science Annex, Room 420, 29 Peachtree Center Ave NE, Atlanta, GA 30303, United States.
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13
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Evans MC, Campbell RE, Anderson GM. Physiological regulation of leptin as an integrative signal of reproductive readiness. Curr Opin Pharmacol 2022; 67:102321. [PMID: 36427399 DOI: 10.1016/j.coph.2022.102321] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2022] [Accepted: 10/24/2022] [Indexed: 11/23/2022]
Abstract
Reproductive function is tightly regulated by both environmental and physiological factors. The adipose-derived hormone leptin has been identified as one such critical factor that relays information about peripheral energy availability to the centrally-governed HPG axis to ensure there is sufficient energy availability to support the high energy demands of mammalian reproduction. In the absence of adequate central leptin signaling, reproductive function is suppressed. While leptin levels are predominantly regulated by adiposity, circulating leptin levels are also under the modulatory influence of other factors, such as stress system activation, circadian rhythmicity, and immune activation and the inflammatory response. Furthermore, changes in leptin sensitivity can affect the degree to which leptin exerts its influence on the neuroendocrine reproductive axis. This review will discuss the different mechanisms by which leptin serves to integrate and relay information about metabolic, psychological, environmental and immune conditions to the central neuronal network that governs reproductive function.
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Affiliation(s)
- Maggie C Evans
- Centre for Neuroendocrinology, University of Otago School of Biomedical Sciences, Dunedin, New Zealand
| | - Rebecca E Campbell
- Centre for Neuroendocrinology, University of Otago School of Biomedical Sciences, Dunedin, New Zealand
| | - Greg M Anderson
- Centre for Neuroendocrinology, University of Otago School of Biomedical Sciences, Dunedin, New Zealand.
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14
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Krishna AG, Goyal N, Ram D, Rajan AK, Kshitiz KK. Hunger Hormones in Disruptive Mood Dysregulation Disorder in Adolescents: An Exploratory Study. ADOLESCENT PSYCHIATRY 2022. [DOI: 10.2174/2210676612666220415112851] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Background:
Hunger hormones, including ghrelin and leptin, are associated with appetitive behaviors in various psychiatric disorders. Biochemical and hormonal status in disruptive mood dysregulation disorder (DMDD) in adolescents is largely unexplored.
Objectives:
The study aimed to assess levels of leptin and ghrelin and find their association with lipid profiles in adolescents with DMDD.
Methods:
Twenty adolescents with a DSM 5 diagnosis of DMDD with age and gender-matched 19 healthy controls were recruited, followed by clinical assessment. They were assessed for leptin, ghrelin, and lipid profiles, respectively.
Results:
Adolescents with DMDD were comparable in age, education, family income, domicile status, psychiatric illness in the family, and body mass index (BMI) with matched controls. There was no difference in mean lipid profile and ghrelin in both groups. However, the DMDD group had statistically significant higher mean level of leptin as compared to the control group (t=1.84, p < 0.05). As measured by the Modified Overt Aggression Scale in DMDD, aggression showed a significant positive correlation with measures of lipid profile.
Conclusion:
Adolescents with DMDD have elevated serum leptin levels. Further research is needed to confirm this finding.
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Affiliation(s)
| | - Nishant Goyal
- Associate Professor of Psychiatry, Centre for Child and Adolescent Psychiatry, Central Institute of Psychiatry, Ranchi
| | - Dushad Ram
- Associate Professor of Psychiatry, College of Medicine, Shaqra University, Shaqra
| | | | - K. K. Kshitiz
- Professor of Biochemistry, Central Institute of Psychiatry, Ranchi
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15
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Bansal S, Kharbanda C, Aneja P. Role and significance of ghrelin and leptin in hunger, satiety, and energy homeostasis. JOURNAL OF THE SCIENTIFIC SOCIETY 2022. [DOI: 10.4103/jss.jss_126_21] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
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16
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Abstract
The modern way of life has dramatically affected our biological rhythms. Circadian rhythms, which are generated by an endogenous circadian clock, are observed in a large number of physiological functions including metabolism. Proper peripheral clock synchronization by different signals including appropriate feeding/fasting cycles is essential to coordinate and temporally gate metabolic processes. In this chapter, we emphasize the importance of nutrient sensing by peripheral clocks and highlight the major role of peripheral and central clock communication to locally regulate metabolic processes and ensure optimal energy storage and expenditure. As a consequence, changes in eating behavior and/or bedtime, as occurs upon shift work and jet lag, have direct consequences on metabolism and participate in the increasing prevalence of obesity and associated metabolic diseases such as type 2 diabetes and non-alcoholic fatty liver disease. In this setting, time-restricted feeding has been suggested as an efficient approach to ameliorate metabolic parameters and control body weight.
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Affiliation(s)
- Yasmine Sebti
- Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011-EGID, Lille, France
| | - Aurore Hebras
- Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011-EGID, Lille, France
| | - Benoit Pourcet
- Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011-EGID, Lille, France
| | - Bart Staels
- Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011-EGID, Lille, France.
| | - Hélène Duez
- Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011-EGID, Lille, France
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17
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Amin MR, Pednekar DD, Azgomi HF, van Wietmarschen H, Aschbacher K, Faghih RT. Sparse System Identification of Leptin Dynamics in Women With Obesity. Front Endocrinol (Lausanne) 2022; 13:769951. [PMID: 35480480 PMCID: PMC9037068 DOI: 10.3389/fendo.2022.769951] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/02/2021] [Accepted: 01/24/2022] [Indexed: 01/03/2023] Open
Abstract
The prevalence of obesity is increasing around the world at an alarming rate. The interplay of the hormone leptin with the hypothalamus-pituitary-adrenal axis plays an important role in regulating energy balance, thereby contributing to obesity. This study presents a mathematical model, which describes hormonal behavior leading to an energy abnormal equilibrium that contributes to obesity. To this end, we analyze the behavior of two neuroendocrine hormones, leptin and cortisol, in a cohort of women with obesity, with simplified minimal state-space modeling. Using a system theoretic approach, coordinate descent method, and sparse recovery, we deconvolved the serum leptin-cortisol levels. Accordingly, we estimate the secretion patterns, timings, amplitudes, number of underlying pulses, infusion, and clearance rates of hormones in eighteen premenopausal women with obesity. Our results show that minimal state-space model was able to successfully capture the leptin and cortisol sparse dynamics with the multiple correlation coefficients greater than 0.83 and 0.87, respectively. Furthermore, the Granger causality test demonstrated a negative prospective predictive relationship between leptin and cortisol, 14 of 18 women. These results indicate that increases in cortisol are prospectively associated with reductions in leptin and vice versa, suggesting a bidirectional negative inhibitory relationship. As dysregulation of leptin may result in an abnormality in satiety and thereby associated to obesity, the investigation of leptin-cortisol sparse dynamics may offer a better diagnostic methodology to improve better treatments plans for individuals with obesity.
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Affiliation(s)
- Md Rafiul Amin
- Department of Electrical and Computer Engineering, University of Houston, Houston, TX, United States
| | - Divesh Deepak Pednekar
- Department of Electrical and Computer Engineering, University of Houston, Houston, TX, United States
| | - Hamid Fekri Azgomi
- Department of Electrical and Computer Engineering, University of Houston, Houston, TX, United States
| | | | - Kirstin Aschbacher
- Department of Psychiatry, Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, United States
| | - Rose T Faghih
- Department of Electrical and Computer Engineering, University of Houston, Houston, TX, United States
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18
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Ojeda ML, Nogales F, Romero-Herrera I, Carreras O. Fetal Programming Is Deeply Related to Maternal Selenium Status and Oxidative Balance; Experimental Offspring Health Repercussions. Nutrients 2021; 13:nu13062085. [PMID: 34207090 PMCID: PMC8233903 DOI: 10.3390/nu13062085] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2021] [Revised: 06/08/2021] [Accepted: 06/15/2021] [Indexed: 12/12/2022] Open
Abstract
Nutrients consumed by mothers during pregnancy and lactation can exert permanent effects upon infant developing tissues, which could represent an important risk factor for diseases during adulthood. One of the important nutrients that contributes to regulating the cell cycle and tissue development and functionality is the trace element selenium (Se). Maternal Se requirements increase during gestation and lactation. Se performs its biological action by forming part of 25 selenoproteins, most of which have antioxidant properties, such as glutathione peroxidases (GPxs) and selenoprotein P (SELENOP). These are also related to endocrine regulation, appetite, growth and energy homeostasis. In experimental studies, it has been found that low dietary maternal Se supply leads to an important oxidative disruption in dams and in their progeny. This oxidative stress deeply affects gestational parameters, and leads to intrauterine growth retardation and abnormal development of tissues, which is related to endocrine metabolic imbalance. Childhood pathologies related to oxidative stress during pregnancy and/or lactation, leading to metabolic programing disorders like fetal alcohol spectrum disorders (FASD), have been associated with a low maternal Se status and intrauterine growth retardation. In this context, Se supplementation therapy to alcoholic dams avoids growth retardation, hepatic oxidation and improves gestational and breastfeeding parameters in FASD pups. This review is focused on the important role that Se plays during intrauterine and breastfeeding development, in order to highlight it as a marker and/or a nutritional strategy to avoid diverse fetal programming disorders related to oxidative stress.
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19
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Andersson B, Tan EP, McGreal SR, Apte U, Hanover JA, Slawson C, Lagerlöf O. O-GlcNAc cycling mediates energy balance by regulating caloric memory. Appetite 2021; 165:105320. [PMID: 34029673 DOI: 10.1016/j.appet.2021.105320] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2020] [Revised: 05/12/2021] [Accepted: 05/13/2021] [Indexed: 12/26/2022]
Abstract
Caloric need has long been thought a major driver of appetite. However, it is unclear whether caloric need regulates appetite in environments offered by many societies today where there is no shortage of food. Here we observed that wildtype mice with free access to food did not match calorie intake to calorie expenditure. While the size of a meal affected subsequent intake, there was no compensation for earlier under- or over-consumption. To test how spontaneous eating is subject to caloric control, we manipulated O-linked β-N-acetylglucosamine (O-GlcNAc), an energy signal inside cells dependent on nutrient access and metabolic hormones. Genetic and pharmacological manipulation in mice increasing or decreasing O-GlcNAcylation regulated daily intake by controlling meal size. Meal size was affected at least in part due to faster eating speed. Without affecting meal frequency, O-GlcNAc disrupted the effect of caloric consumption on future intake. Across days, energy balance was improved upon increased O-GlcNAc levels and impaired upon removal of O-GlcNAcylation. Rather than affecting a perceived need for calories, O-GlcNAc regulates how a meal affects future intake, suggesting that O-GlcNAc mediates a caloric memory and subsequently energy balance.
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Affiliation(s)
- Björn Andersson
- Department of Pediatric Surgery, Uppsala University Hospital, 75185, Uppsala, Sweden
| | - Ee Phie Tan
- Sanford Burnham Prebys Medical Discovery Institute, 92037, CA, USA
| | - Steven R McGreal
- Department of Pharmacology, Toxicology and Therapeutics, Kansas University, 66160, KS, USA
| | - Udayan Apte
- Department of Pharmacology, Toxicology and Therapeutics, Kansas University, 66160, KS, USA
| | - John A Hanover
- National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Health, 20892, MD, USA
| | - Chad Slawson
- Department of Biochemistry and Molecular Biology, Kansas University, 66160, KS, USA
| | - Olof Lagerlöf
- Department of Clinical Sciences, Umeå University, 901 87, Umeå, Sweden; Department of Integrative Medical Biology, Umeå University, 901 87, Umeå, Sweden; Wallenberg Centre for Molecular Medicine, Umeå University, 901 87, Umeå, Sweden.
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20
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The effect of an orally-dosed Caralluma Fimbriata extract on appetite control and body composition in overweight adults. Sci Rep 2021; 11:6791. [PMID: 33762661 PMCID: PMC7991653 DOI: 10.1038/s41598-021-86108-2] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2020] [Accepted: 02/25/2021] [Indexed: 11/09/2022] Open
Abstract
To examine the effect of a Caralluma Fimbriata extract (CFE) on biomarkers of satiety and body composition in overweight adults. A double-blind, randomised, placebo controlled trial to examine the effect of a Caralluma Fimbriata extract (CFE) on biomarkers of satiety and body composition in overweight adults. Eighty-three men and women aged between 20 and 50 years of age completed 16 weeks of daily supplementation with either CFE or placebo. Plasma cardiometabolic (lipid profile, glucose, insulin) and satiety (ghrelin, leptin, neuropeptideY) biomarkers, body composition, diet history and gastrointenstinal function were assessed at baseline, weeks 4, 8, 12 and 16. Subjects in the CFE and placebo groups were well matched and predominatly female 93% and 87.5%, with a mean age of 40.9 ± 6.7 and 39.5 ± 7.5 years and body mass index (BMI) of 30.0 ± 3.1 and 30.2 ± 2.9 kg/m2 respectively. There was a significant difference in plasma leptin concentration change between groups at week 16 (p = 0.04), with the placebo group increasing concentration (2.27 ± 4.80 ng/mL) while the CFE group (0.05 ± 4.69 ng/mL) remained the same. At week 16, the CFE group had significantly reduced their calorie intake from baseline compared to the placebo group (245 cal vs 15.8 cal respectively p < 0.01). The CFE group also had a significant reduction in waist circumference of 2.7 cm compared to an increase of 0.3 cm in the placebo group (p = 0.02). A weight increase from baseline was seen in the placebo group that was not observed in the CFE group (1.33 kg weight gain vs 0.37 kg weight loss respectively; p = 0.03). The placebo group also had a significant increase in fat mass, android fat mass, BMI and leptin compared to the CFE group (p = 0.04, 0.02, < 0.01 respectively). CFE was effective at maintaining bodyweight during a non-calorie controlled diet compared to a placebo. The mechanism responsible for this action is requiring further research and could be due to an increase in satiety receptor sensitivity.
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21
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Mosavat M, Mirsanjari M, Arabiat D, Smyth A, Whitehead L. The Role of Sleep Curtailment on Leptin Levels in Obesity and Diabetes Mellitus. Obes Facts 2021; 14:214-221. [PMID: 33756469 PMCID: PMC8138234 DOI: 10.1159/000514095] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/30/2020] [Accepted: 12/23/2020] [Indexed: 12/15/2022] Open
Abstract
Emerging evidence has identified sleep as a significant, but modifiable, risk factor for metabolic syndrome, diabetes, and obesity. Leptin, an adipocyte-derived peptide and a regulator of food intake and energy expenditure, has been shown to be associated with a short sleep duration in the pathophysiology of obesity and consequently type 2 diabetes. This review focuses on the current evidence indicating the effects of a short sleep duration on the regulation of leptin concentration in association with obesity and diabetes mellitus. In summary, the evidence suggests that sleep deprivation, by affecting leptin regulation, may lead to obesity and consequently development of type 2 diabetes through increased appetite and food intake. However, findings on the role of leptin in diabetes due to sleep deprivation are contradictory, and further studies with larger sample sizes are needed to confirm previous findings.
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Affiliation(s)
- Maryam Mosavat
- School of Nursing and Midwifery, Edith Cowan University, Joondalup, Washington, Australia,
| | - Mitra Mirsanjari
- Mazandaran University of Medical Sciences, Emam Khomeini Hospital, Mazandaran, Iran
| | - Diana Arabiat
- School of Nursing and Midwifery, Edith Cowan University, Joondalup, Washington, Australia
- Maternal and Child Nursing Department, The University of Jordan, Amman, Jordan
| | - Aisling Smyth
- School of Nursing and Midwifery, Edith Cowan University, Joondalup, Washington, Australia
| | - Lisa Whitehead
- School of Nursing and Midwifery, Edith Cowan University, Joondalup, Washington, Australia
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22
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Patsalos O, Keeler J, Schmidt U, Penninx BWJH, Young AH, Himmerich H. Diet, Obesity, and Depression: A Systematic Review. J Pers Med 2021; 11:176. [PMID: 33802480 PMCID: PMC7999659 DOI: 10.3390/jpm11030176] [Citation(s) in RCA: 59] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2021] [Revised: 02/19/2021] [Accepted: 02/24/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Obesity and depression co-occur in a significant proportion of the population. Mechanisms linking the two disorders include the immune and the endocrine system, psychological and social mechanisms. The aim of this systematic review was to ascertain whether weight loss through dietary interventions has the additional effect of ameliorating depressive symptoms in obese patients. METHODS We systematically searched three databases (Pubmed, Medline, Embase) for longitudinal clinical trials testing a dietary intervention in people with obesity and depression or symptoms of depression. RESULTS Twenty-four longitudinal clinical studies met the eligibility criteria with a total of 3244 included patients. Seventeen studies examined the effects of calorie-restricted diets and eight studies examined dietary supplements (two studies examined both). Only three studies examined people with a diagnosis of both obesity and depression. The majority of studies showed that interventions using a calorie-restricted diet resulted in decreases in depression scores, with effect sizes between ≈0.2 and ≈0.6. The results were less clear for dietary supplements. CONCLUSIONS People with obesity and depression appear to be a specific subgroup of depressed patients in which calorie-restricted diets might constitute a promising personalized treatment approach. The reduction of depressive symptoms may be related to immunoendocrine and psychosocial mechanisms.
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Affiliation(s)
- Olivia Patsalos
- Department of Psychological Medicine, Institute of Psychiatry, Psychology & Neuroscience, King’s College London, London SE5 8AF, UK; (O.P.); (J.K.); (U.S.); (A.H.Y.)
| | - Johanna Keeler
- Department of Psychological Medicine, Institute of Psychiatry, Psychology & Neuroscience, King’s College London, London SE5 8AF, UK; (O.P.); (J.K.); (U.S.); (A.H.Y.)
| | - Ulrike Schmidt
- Department of Psychological Medicine, Institute of Psychiatry, Psychology & Neuroscience, King’s College London, London SE5 8AF, UK; (O.P.); (J.K.); (U.S.); (A.H.Y.)
- South London and Maudsley NHS Foundation Trust, London SE5 8AZ, UK
| | - Brenda W. J. H. Penninx
- Department of Psychiatry, Amsterdam Public Health Research Institute, Amsterdam UMC, Vrije Universiteit, 1081 BT Amsterdam, The Netherlands;
| | - Allan H. Young
- Department of Psychological Medicine, Institute of Psychiatry, Psychology & Neuroscience, King’s College London, London SE5 8AF, UK; (O.P.); (J.K.); (U.S.); (A.H.Y.)
- South London and Maudsley NHS Foundation Trust, London SE5 8AZ, UK
| | - Hubertus Himmerich
- Department of Psychological Medicine, Institute of Psychiatry, Psychology & Neuroscience, King’s College London, London SE5 8AF, UK; (O.P.); (J.K.); (U.S.); (A.H.Y.)
- South London and Maudsley NHS Foundation Trust, London SE5 8AZ, UK
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23
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Browning BD, Schwandt ML, Farokhnia M, Deschaine SL, Hodgkinson CA, Leggio L. Leptin Gene and Leptin Receptor Gene Polymorphisms in Alcohol Use Disorder: Findings Related to Psychopathology. Front Psychiatry 2021; 12:723059. [PMID: 34421692 PMCID: PMC8377199 DOI: 10.3389/fpsyt.2021.723059] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/09/2021] [Accepted: 07/12/2021] [Indexed: 11/13/2022] Open
Abstract
Comorbidity between alcohol use disorder (AUD) and other addictive and psychiatric disorders is highly prevalent and disabling; however, the underlying biological correlates are not fully understood. Leptin is a peptide hormone known for its role in energy homeostasis and food intake. Furthermore, leptin plays a key role in the activity of the hypothalamic-pituitary-adrenal (HPA) axis and of several neurotransmitter systems that regulate emotionality and behavior. However, human studies that have investigated circulating leptin levels in relation to AUD and affective disorders, such as anxiety and depression, are conflicting. Genetic-based analyses of the leptin gene (LEP) and leptin receptor gene (LEPR) have the potential of providing more insight into the potential role of the leptin system in AUD and comorbid psychopathology. The aim of the current study was to investigate whether genotypic variations at LEP and LEPR are associated with measures of alcohol use, nicotine use, anxiety, and depression, all of which represent common comorbidities with AUD. Haplotype association analyses were performed, using data from participants enrolled in screening and natural history protocols at the National Institute on Alcohol Abuse and Alcoholism (NIAAA). Analyses were performed separately in European Americans and African Americans due to the variation in haplotype diversity for most genes between these groups. In the European American group, one LEP haplotype (EB2H4) was associated with lower odds of having a current AUD diagnosis, two LEPR haplotypes (EB7H3, EB8H3) were associated with lower cigarette pack years and two LEPR haplotypes (EB7H2, EB8H2) were associated with higher State-Trait Anxiety Inventory (STAI-T) scores. In the African American group, one LEP haplotype (AB2H8) was associated with higher cigarette pack years and one LEP haplotype (AB3H2) was associated with lower Fagerström Test for Nicotine Dependence (FTND) scores. Overall, this study found that variations in the leptin and leptin receptor genes are associated with measures of alcohol use, nicotine use, and anxiety. While this preliminary study adds support for a role of the leptin system in AUD and psychopathologies, additional studies are required to fully understand the underlying mechanisms and potential therapeutic implications of these findings.
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Affiliation(s)
- Brittney D Browning
- Clinical Psychoneuroendocrinology and Neuropsychopharmacology Section, Translational Addiction Medicine Branch, National Institute on Drug Abuse Intramural Research Program and National Institute on Alcohol Abuse and Alcoholism Division of Intramural Clinical and Biological Research, National Institutes of Health, Baltimore, MD, United States
| | - Melanie L Schwandt
- Office of the Clinical Director, National Institute on Alcohol Abuse and Alcoholism Division of Intramural Clinical and Biological Research, National Institutes of Health, Bethesda, MD, United States
| | - Mehdi Farokhnia
- Clinical Psychoneuroendocrinology and Neuropsychopharmacology Section, Translational Addiction Medicine Branch, National Institute on Drug Abuse Intramural Research Program and National Institute on Alcohol Abuse and Alcoholism Division of Intramural Clinical and Biological Research, National Institutes of Health, Baltimore, MD, United States.,Department of Mental Health, Johns Hopkins Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, United States
| | - Sara L Deschaine
- Clinical Psychoneuroendocrinology and Neuropsychopharmacology Section, Translational Addiction Medicine Branch, National Institute on Drug Abuse Intramural Research Program and National Institute on Alcohol Abuse and Alcoholism Division of Intramural Clinical and Biological Research, National Institutes of Health, Baltimore, MD, United States
| | - Colin A Hodgkinson
- Laboratory of Neurogenetics, National Institute on Alcohol Abuse and Alcoholism Division of Intramural Clinical and Biological Research, National Institutes of Health, Rockville, MD, United States
| | - Lorenzo Leggio
- Clinical Psychoneuroendocrinology and Neuropsychopharmacology Section, Translational Addiction Medicine Branch, National Institute on Drug Abuse Intramural Research Program and National Institute on Alcohol Abuse and Alcoholism Division of Intramural Clinical and Biological Research, National Institutes of Health, Baltimore, MD, United States.,Medication Development Program, National Institute on Drug Abuse Intramural Research Program, National Institutes of Health, Baltimore, MD, United States.,Center for Alcohol and Addiction Studies, Department of Behavioral and Social Sciences, Brown University School of Public Health, Providence, RI, United States.,Division of Addiction Medicine, Department of Medicine, School of Medicine, Johns Hopkins University, Baltimore, MD, United States.,Department of Neuroscience, Georgetown University Medical Center, Washington, DC, United States
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24
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Martínez-Sánchez N. There and Back Again: Leptin Actions in White Adipose Tissue. Int J Mol Sci 2020; 21:ijms21176039. [PMID: 32839413 PMCID: PMC7503240 DOI: 10.3390/ijms21176039] [Citation(s) in RCA: 75] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2020] [Revised: 08/17/2020] [Accepted: 08/18/2020] [Indexed: 12/13/2022] Open
Abstract
Leptin is a hormone discovered almost 30 years ago with important implications in metabolism. It is primarily produced by white adipose tissue (WAT) in proportion to the amount of fat. The discovery of leptin was a turning point for two principle reasons: on one hand, it generated promising expectations for the treatment of the obesity, and on the other, it changed the classical concept that white adipose tissue was simply an inert storage organ. Thus, adipocytes in WAT produce the majority of leptin and, although its primary role is the regulation of fat stores by controlling lipolysis and lipogenesis, this hormone also has implications in other physiological processes within WAT, such as apoptosis, browning and inflammation. Although a massive number of questions related to leptin actions have been answered, the necessity for further clarification facilitates constantly renewing interest in this hormone and its pathways. In this review, leptin actions in white adipose tissue will be summarized in the context of obesity.
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25
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Boutari C, Pappas PD, Mintziori G, Nigdelis MP, Athanasiadis L, Goulis DG, Mantzoros CS. The effect of underweight on female and male reproduction. Metabolism 2020; 107:154229. [PMID: 32289345 DOI: 10.1016/j.metabol.2020.154229] [Citation(s) in RCA: 60] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/19/2019] [Revised: 04/09/2020] [Accepted: 04/10/2020] [Indexed: 12/13/2022]
Abstract
Chronic energy deficiency can impair the hypothalamic-pituitary-gonadal (HPG) axis and lead to hypothalamic anovulation in underweight women. This review presents the syndromes related to underweight status that are associated with infertility, summarizes the underlying mechanisms, and reviews the available treatment options. Eating disorders, such as anorexia nervosa (AN), constitute the most common cause of infertility in underweight women, who, in addition, experience miscarriages, and sexual dysfunction. The relative energy deficiency in sports (RED-S; former terminology: athlete's triad) involves menstrual dysfunction due to low energy availability, which results in anovulation. Moreover, lipodystrophies, malnutrition, starvation, systematic illnesses (malignancies, endocrinopathies, infectious diseases, advanced chronic diseases, neurologic illnesses), and the utilization of drugs can cause excessive weight loss. They may result in fertility problems due to the loss of adipose tissue and the subsequent hormonal disturbances. Each of these conditions requires multidisciplinary management. Nutritional counseling should target the restoration of energy balance by increasing intake and reducing output. Medical treatment, recommended only for patients who did not respond to standard treatment, may include antipsychotics, antidepressants, or leptin administration. Finally, psychiatric treatment is considered an integral part of the standard treatment.
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Affiliation(s)
- Chrysoula Boutari
- Department of Medicine, Boston VA Healthcare System and Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA
| | - Panagiotis D Pappas
- Unit of Reproductive Endocrinology, 1(st) Department of Obstetrics and Gynecology, Medical School, Aristotle University of Thessaloniki, Greece
| | - Gesthimani Mintziori
- Unit of Reproductive Endocrinology, 1(st) Department of Obstetrics and Gynecology, Medical School, Aristotle University of Thessaloniki, Greece
| | - Meletios P Nigdelis
- Unit of Reproductive Endocrinology, 1(st) Department of Obstetrics and Gynecology, Medical School, Aristotle University of Thessaloniki, Greece
| | - Loukas Athanasiadis
- 3(rd) Department of Psychiatry, Medical School, Aristotle University of Thessaloniki, Greece
| | - Dimitrios G Goulis
- Unit of Reproductive Endocrinology, 1(st) Department of Obstetrics and Gynecology, Medical School, Aristotle University of Thessaloniki, Greece
| | - Christos S Mantzoros
- Department of Medicine, Boston VA Healthcare System and Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
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Akram F, Gragnoli C, Raheja UK, Snitker S, Lowry CA, Sterns-Yoder KA, Hoisington AJ, Brenner LA, Saunders E, Stiller JW, Ryan KA, Rohan KJ, Mitchell BD, Postolache TT. Seasonal affective disorder and seasonal changes in weight and sleep duration are inversely associated with plasma adiponectin levels. J Psychiatr Res 2020; 122:97-104. [PMID: 31981963 PMCID: PMC7024547 DOI: 10.1016/j.jpsychires.2019.12.016] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/10/2019] [Revised: 12/25/2019] [Accepted: 12/30/2019] [Indexed: 12/15/2022]
Abstract
Overlapping pathways between mood and metabolic regulation have increasingly been reported. Although impaired regulation of adiponectin, a major metabolism-regulating hormone, has been implicated in major depressive disorder, its role in seasonal changes in mood and seasonal affective disorder-winter type (SAD), a disorder characterized by onset of mood impairment and metabolic dysregulation (e.g., carbohydrate craving and weight gain) in fall/winter and spontaneous alleviation in spring/summer, has not been previously studied. We studied a convenience sample of 636 Old Order Amish (mean (± SD), 53.6 (±14.8) years; 50.1% males), a population with self-imposed restriction on network electric light at home, and low prevalence of total SAD (t-SAD = syndromal + subsyndromal). We calculated the global seasonality score (GSS), estimated SAD and subsyndromal-SAD after obtaining Seasonal Pattern Assessment Questionnaires (SPAQs), and measured overnight fasting plasma adiponectin levels. We then tested associations between plasma adiponectin levels and GSS, t-SAD, winter-summer difference in self-reported sleep duration, and self-reported seasonal weight change, by using analysis of co-variance (ANCOVA) and linear regression analysis after adjusting for age, gender, and BMI. Participants with t-SAD (N = 14; 2.2%) had significantly lower plasma adiponectin levels (mean ± SEM, 8.76 ± 1.56 μg/mL) than those without t-SAD (mean ± SEM, 11.93 ± 0.22 μg/mL) (p = 0.035). In addition, there was significant negative association between adiponectin levels and winter-summer difference in self-reported sleep duration (p = 0.025) and between adiponectin levels and self-reported seasonal change in weight (p = 0.006). There was no significant association between GSS and adiponectin levels (p = 0.88). To our knowledge, this is the first study testing the association of SAD with adiponectin levels. Replication and extension of our findings longitudinally and, then, interventionally, may implicate low adiponectin as a novel target for therapeutic intervention in SAD.
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Affiliation(s)
- Faisal Akram
- Mood and Anxiety Program, University of Maryland School of Medicine, Baltimore, MD, USA,Saint Elizabeths Hospital, DC Department of Behavioral Health, Washington, DC, USA
| | - Claudia Gragnoli
- Division of Endocrinology, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA, USA,Public Health Sciences, Penn State College of Medicine, Hershey, PA, USA,Molecular Biology Laboratory, Bios Biotech Multi-Diagnostic Health Center, Rome, Italy
| | - Uttam K. Raheja
- Mood and Anxiety Program, University of Maryland School of Medicine, Baltimore, MD, USA,Saint Elizabeths Hospital, DC Department of Behavioral Health, Washington, DC, USA
| | - Soren Snitker
- Division of Endocrinology, Diabetes and Nutrition, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA,Amish Research Clinic of the University of Maryland, Lancaster, PA, USA
| | - Christopher A. Lowry
- Veterans Health Administration, Rocky Mountain Mental Illness Research Education and Clinical Center (MIRECC), Rocky Mountain Regional Veterans Affairs Medical Center (RMRVAMC), Aurora, CO, USA,Department of Physical Medicine & Rehabilitation and Center for Neuroscience, University of Colorado Anschutz Medical Campus, Aurora, CO, USA,Military and Veteran Microbiome: Consortium for Research and Education (MVM-CoRE), Aurora, CO, USA,Department of Integrative Physiology and Center for Neuroscience, University of Colorado Boulder, Boulder, CO, USA
| | - Kelly A. Sterns-Yoder
- Veterans Health Administration, Rocky Mountain Mental Illness Research Education and Clinical Center (MIRECC), Rocky Mountain Regional Veterans Affairs Medical Center (RMRVAMC), Aurora, CO, USA,Military and Veteran Microbiome: Consortium for Research and Education (MVM-CoRE), Aurora, CO, USA,Department of Physical Medicine & Rehabilitation, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Andrew J. Hoisington
- Military and Veteran Microbiome: Consortium for Research and Education (MVM-CoRE), Aurora, CO, USA,Department of Systems Engineering, Air Force Institute of Technology, Wright-Patterson AFB, OH, USA
| | - Lisa A. Brenner
- Veterans Health Administration, Rocky Mountain Mental Illness Research Education and Clinical Center (MIRECC), Rocky Mountain Regional Veterans Affairs Medical Center (RMRVAMC), Aurora, CO, USA,Military and Veteran Microbiome: Consortium for Research and Education (MVM-CoRE), Aurora, CO, USA,Department of Physical Medicine & Rehabilitation, University of Colorado Anschutz Medical Campus, Aurora, CO, USA,Departments of Psychiatry & Neurology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Erika Saunders
- Department of Psychiatry, Penn State University, Hershey, PA, USA
| | - John W. Stiller
- Mood and Anxiety Program, University of Maryland School of Medicine, Baltimore, MD, USA,Saint Elizabeths Hospital, DC Department of Behavioral Health, Washington, DC, USA
| | - Kathleen A. Ryan
- Program for Personalized and Genomic Medicine, Division of Endocrinology, Diabetes and Nutrition, Department of Medicine, University of Maryland, School of Medicine, Baltimore, MD, USA,Geriatrics Research and Education Clinical Center, Baltimore, MD, USA,Baltimore Veterans Administration Medical Center, Baltimore, MD, USA
| | - Kelly J. Rohan
- Department of Psychological Science, University of Vermont, Burlington, VT, USA
| | - Braxton D. Mitchell
- Program for Personalized and Genomic Medicine, Division of Endocrinology, Diabetes and Nutrition, Department of Medicine, University of Maryland, School of Medicine, Baltimore, MD, USA,Geriatrics Research and Education Clinical Center, Baltimore, MD, USA,Baltimore Veterans Administration Medical Center, Baltimore, MD, USA
| | - Teodor T. Postolache
- Mood and Anxiety Program, University of Maryland School of Medicine, Baltimore, MD, USA,Saint Elizabeths Hospital, DC Department of Behavioral Health, Washington, DC, USA,Veterans Health Administration, Rocky Mountain Mental Illness Research Education and Clinical Center (MIRECC), Rocky Mountain Regional Veterans Affairs Medical Center (RMRVAMC), Aurora, CO, USA,Department of Physical Medicine & Rehabilitation, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
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Boutari C, Mantzoros CS. Adiponectin and leptin in the diagnosis and therapy of NAFLD. Metabolism 2020; 103:154028. [PMID: 31785257 DOI: 10.1016/j.metabol.2019.154028] [Citation(s) in RCA: 64] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/21/2019] [Accepted: 11/22/2019] [Indexed: 12/11/2022]
Affiliation(s)
- Chrysoula Boutari
- Department of Internal Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, Boston, MA 02215, USA
| | - Christos S Mantzoros
- Department of Internal Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, Boston, MA 02215, USA; Section of Endocrinology, Diabetes and Metabolism, Boston VA Healthcare System, 150 South Huntington Avenue, Boston, MA 02130, USA.
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28
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The Novel Perspectives of Adipokines on Brain Health. Int J Mol Sci 2019; 20:ijms20225638. [PMID: 31718027 PMCID: PMC6887733 DOI: 10.3390/ijms20225638] [Citation(s) in RCA: 65] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2019] [Revised: 11/05/2019] [Accepted: 11/06/2019] [Indexed: 12/13/2022] Open
Abstract
First seen as a fat-storage tissue, the adipose tissue is considered as a critical player in the endocrine system. Precisely, adipose tissue can produce an array of bioactive factors, including cytokines, lipids, and extracellular vesicles, which target various systemic organ systems to regulate metabolism, homeostasis, and immune response. The global effects of adipokines on metabolic events are well defined, but their impacts on brain function and pathology remain poorly defined. Receptors of adipokines are widely expressed in the brain. Mounting evidence has shown that leptin and adiponectin can cross the blood–brain barrier, while evidence for newly identified adipokines is limited. Significantly, adipocyte secretion is liable to nutritional and metabolic states, where defective circuitry, impaired neuroplasticity, and elevated neuroinflammation are symptomatic. Essentially, neurotrophic and anti-inflammatory properties of adipokines underlie their neuroprotective roles in neurodegenerative diseases. Besides, adipocyte-secreted lipids in the bloodstream can act endocrine on the distant organs. In this article, we have reviewed five adipokines (leptin, adiponectin, chemerin, apelin, visfatin) and two lipokines (palmitoleic acid and lysophosphatidic acid) on their roles involving in eating behavior, neurotrophic and neuroprotective factors in the brain. Understanding and regulating these adipokines can lead to novel therapeutic strategies to counteract metabolic associated eating disorders and neurodegenerative diseases, thus promote brain health.
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29
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Ghadge AA, Khaire AA. Leptin as a predictive marker for metabolic syndrome. Cytokine 2019; 121:154735. [DOI: 10.1016/j.cyto.2019.154735] [Citation(s) in RCA: 44] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2018] [Revised: 03/16/2019] [Accepted: 05/24/2019] [Indexed: 02/07/2023]
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Turkson S, Kloster A, Hamilton PJ, Neigh GN. Neuroendocrine drivers of risk and resilience: The influence of metabolism & mitochondria. Front Neuroendocrinol 2019; 54:100770. [PMID: 31288042 PMCID: PMC6886586 DOI: 10.1016/j.yfrne.2019.100770] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/02/2019] [Revised: 06/20/2019] [Accepted: 07/03/2019] [Indexed: 02/07/2023]
Abstract
The manifestation of risk versus resilience has been considered from varying perspectives including genetics, epigenetics, early life experiences, and type and intensity of the challenge with which the organism is faced. Although all of these factors are central to determining risk and resilience, the current review focuses on what may be a final common pathway: metabolism. When an organism is faced with a perturbation to the environment, whether internal or external, appropriate energy allocation is essential to resolving the divergence from equilibrium. This review examines the potential role of metabolism in the manifestation of stress-induced neural compromise. In addition, this review details the current state of knowledge on neuroendocrine factors which are poised to set the tone of the metabolic response to a systemic challenge. The goal is to provide an essential framework for understanding stress in a metabolic context and appreciation for key neuroendocrine signals.
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Affiliation(s)
- Susie Turkson
- Department of Anatomy & Neurobiology, Virginia Commonwealth University, Richmond, VA, United States
| | - Alix Kloster
- Department of Anatomy & Neurobiology, Virginia Commonwealth University, Richmond, VA, United States
| | - Peter J Hamilton
- Department of Anatomy & Neurobiology, Virginia Commonwealth University, Richmond, VA, United States
| | - Gretchen N Neigh
- Department of Anatomy & Neurobiology, Virginia Commonwealth University, Richmond, VA, United States.
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31
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Abulizi A, Camporez JP, Jurczak MJ, Høyer KF, Zhang D, Cline GW, Samuel VT, Shulman GI, Vatner DF. Adipose glucocorticoid action influences whole-body metabolism via modulation of hepatic insulin action. FASEB J 2019; 33:8174-8185. [PMID: 30922125 PMCID: PMC6593882 DOI: 10.1096/fj.201802706r] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2018] [Accepted: 03/18/2019] [Indexed: 12/14/2022]
Abstract
The connection between adipose glucocorticoid action and whole-body metabolism is incompletely understood. Thus, we generated adipose tissue-specific glucocorticoid receptor-knockout (Ad-GcR-/-) mice to explore potential mechanisms. Ad-GcR-/- mice had a lower concentration of fasting plasma nonesterified fatty acids and less hepatic steatosis. This was associated with increased protein kinase B phosphorylation and increased hepatic glycogen synthesis after an oral glucose challenge. High-fat diet (HFD)-fed Ad-GcR-/- mice were protected against the development of hepatic steatosis and diacylglycerol-PKCε-induced impairments in hepatic insulin signaling. Under hyperinsulinemic-euglycemic conditions, hepatic insulin response was ∼10-fold higher in HFD-fed Ad-GcR-/- mice. Insulin-mediated suppression of adipose lipolysis was improved by 40% in Ad-GcR-/- mice. Adipose triglyceride lipase expression was decreased and insulin-mediated perilipin dephosphorylation was increased in Ad-GcR-/- mice. In metabolic cages, food intake decreased by 3 kcal/kg per hour in Ad-GcR-/- mice. Therefore, physiologic adipose glucocorticoid action appears to drive hepatic lipid accumulation during stressors such as fasting. The resultant hepatic insulin resistance prevents hepatic glycogen synthesis, preserving glucose for glucose-dependent organs. Absence of adipose glucocorticoid action attenuates HFD-induced hepatic insulin resistance; potential explanations for reduction in hepatic steatosis include reductions in adipose lipolysis and food intake.-Abulizi, A., Camporez, J.-P., Jurczak, M. J., Høyer, K. F., Zhang, D., Cline, G. W., Samuel, V. T., Shulman, G. I., Vatner, D. F. Adipose glucocorticoid action influences whole-body metabolism via modulation of hepatic insulin action.
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Affiliation(s)
- Abudukadier Abulizi
- Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut, USA
| | - João-Paulo Camporez
- Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut, USA
| | - Michael J. Jurczak
- Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut, USA
| | - Kasper F. Høyer
- Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut, USA
- Department of Clinical Medicine, Magnetic Resonance Research Centre, Aarhus University, Aarhus, Denmark
| | - Dongyan Zhang
- Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut, USA
| | - Gary W. Cline
- Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut, USA
| | - Varman T. Samuel
- Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut, USA
- Veterans Affairs Medical Center, West Haven, Connecticut, USA
| | - Gerald I. Shulman
- Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut, USA
- Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut, USA
- Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, Connecticut, USA
| | - Daniel F. Vatner
- Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut, USA
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Lundqvist MH, Almby K, Abrahamsson N, Eriksson JW. Is the Brain a Key Player in Glucose Regulation and Development of Type 2 Diabetes? Front Physiol 2019; 10:457. [PMID: 31133864 PMCID: PMC6524713 DOI: 10.3389/fphys.2019.00457] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2018] [Accepted: 04/01/2019] [Indexed: 01/08/2023] Open
Abstract
Ever since Claude Bernards discovery in the mid 19th-century that a lesion in the floor of the third ventricle in dogs led to altered systemic glucose levels, a role of the CNS in whole-body glucose regulation has been acknowledged. However, this finding was later overshadowed by the isolation of pancreatic hormones in the 20th century. Since then, the understanding of glucose homeostasis and pathology has primarily evolved around peripheral mechanism. Due to scientific advances over these last few decades, however, increasing attention has been given to the possibility of the brain as a key player in glucose regulation and the pathogenesis of metabolic disorders such as type 2 diabetes. Studies of animals have enabled detailed neuroanatomical mapping of CNS structures involved in glucose regulation and key neuronal circuits and intracellular pathways have been identified. Furthermore, the development of neuroimaging techniques has provided methods to measure changes of activity in specific CNS regions upon diverse metabolic challenges in humans. In this narrative review, we discuss the available evidence on the topic. We conclude that there is much evidence in favor of active CNS involvement in glucose homeostasis but the relative importance of central vs. peripheral mechanisms remains to be elucidated. An increased understanding of this field may lead to new CNS-focusing pharmacologic strategies in the treatment of type 2 diabetes.
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Affiliation(s)
| | - Kristina Almby
- Department of Medical Sciences, Uppsala University, Uppsala, Sweden
| | | | - Jan W Eriksson
- Department of Medical Sciences, Uppsala University, Uppsala, Sweden
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33
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Ghasemi A, Saeidi J, Azimi-Nejad M, Hashemy SI. Leptin-induced signaling pathways in cancer cell migration and invasion. Cell Oncol (Dordr) 2019; 42:243-260. [PMID: 30877623 DOI: 10.1007/s13402-019-00428-0] [Citation(s) in RCA: 49] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/06/2019] [Indexed: 12/18/2022] Open
Abstract
BACKGROUND Increasing evidence indicates that obesity is associated with tumor development and progression. Leptin is an adipocyte-related hormone with a key role in energy metabolism and whose circulating levels are elevated in obesity. The effect of leptin on cancer progression and metastasis and its underlying mechanisms are still unclear. Leptin can impact various steps in tumor metastasis, including epithelial-mesenchymal transition, cell adhesion to the extracellular matrix (ECM), and proteolysis of ECM components. To do so, leptin binds to its receptor (OB-Rb) to activate signaling pathways and downstream effectors that participate in tumor cell invasion as well as distant metastasis. CONCLUSIONS In this review, we describe metastasis steps in detail and characterize metastasis-related molecules activated by leptin, which may help to develop a roadmap that guides future work. In addition, we conclude that a profound understanding of the fundamental molecular processes that contribute to leptin-induced metastasis may pave the way for the development of new prognostic molecules and appropriate approaches to the treatment of obesity-related cancers.
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Affiliation(s)
- Ahmad Ghasemi
- Department of Basic Medical Sciences, Neyshabur University of Medical Sciences, Neyshabur, Iran
- Department of Clinical Biochemistry, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Jafar Saeidi
- Department of Physiology, School of Basic Science, Neyshabur Branch, Islamic Azad University, Neyshabur, Iran
| | - Mohsen Azimi-Nejad
- Department of Basic Medical Sciences, Neyshabur University of Medical Sciences, Neyshabur, Iran
- Department of Genetic, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Seyed Isaac Hashemy
- Surgical Oncology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.
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Papathanasiou AE, Nolen-Doerr E, Farr OM, Mantzoros CS. GEOFFREY HARRIS PRIZE LECTURE 2018: Novel pathways regulating neuroendocrine function, energy homeostasis and metabolism in humans. Eur J Endocrinol 2019; 180:R59-R71. [PMID: 30475221 PMCID: PMC6378110 DOI: 10.1530/eje-18-0847] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/18/2018] [Accepted: 11/05/2018] [Indexed: 12/12/2022]
Abstract
The discovery of leptin, an adipocyte-secreted hormone, set the stage for unraveling the mechanisms dictating energy homeostasis, revealing adipose tissue as an endocrine system that regulates appetite and body weight. Fluctuating leptin levels provide molecular signals to the brain regarding available energy reserves modulating energy homeostasis and neuroendocrine response in states of leptin deficiency and to a lesser extent in hyperleptinemic states. While leptin replacement therapy fails to provide substantial benefit in common obesity, it is an effective treatment for congenital leptin deficiency and states of acquired leptin deficiency such as lipodystrophy. Current evidence suggests that regulation of eating behavior in humans is not limited to homeostatic mechanisms and that the reward, attention, memory and emotion systems are involved, participating in a complex central nervous system network. It is critical to study these systems for the treatment of typical obesity. Although progress has been made, further studies are required to unravel the physiology, pathophysiology and neurobehavioral mechanisms underlying potential treatments for weight-related problems in humans.
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Affiliation(s)
| | - Eric Nolen-Doerr
- Division of Endocrinology, Beth Israel Deaconess Medical Center/Harvard Medical School, Boston, MA 02215
| | - Olivia M. Farr
- Division of Endocrinology, Beth Israel Deaconess Medical Center/Harvard Medical School, Boston, MA 02215
| | - Christos S. Mantzoros
- Division of Endocrinology, Beth Israel Deaconess Medical Center/Harvard Medical School, Boston, MA 02215
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35
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Forny-Germano L, De Felice FG, Vieira MNDN. The Role of Leptin and Adiponectin in Obesity-Associated Cognitive Decline and Alzheimer's Disease. Front Neurosci 2019; 12:1027. [PMID: 30692905 PMCID: PMC6340072 DOI: 10.3389/fnins.2018.01027] [Citation(s) in RCA: 165] [Impact Index Per Article: 27.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2019] [Accepted: 12/19/2019] [Indexed: 12/14/2022] Open
Abstract
Cross-talk between adipose tissue and central nervous system (CNS) underlies the increased risk of obese people to develop brain diseases such as cognitive and mood disorders. Detailed mechanisms for how peripheral changes caused by adipose tissue accumulation in obesity impact the CNS to cause brain dysfunction are poorly understood. Adipokines are a large group of substances secreted by the white adipose tissue to regulate a wide range of homeostatic processes including, but not limited to, energy metabolism and immunity. Obesity is characterized by a generalized change in the levels of circulating adipokines due to abnormal accumulation and dysfunction of adipose tissue. Altered adipokine levels underlie complications of obesity as well as the increased risk for the development of obesity-related comorbidities such as type 2 diabetes, cardiovascular and neurodegenerative diseases. Here, we review the literature for the role of adipokines as key mediators of the communication between periphery and CNS in health and disease. We will focus on the actions of leptin and adiponectin, two of the most abundant and well studied adipokines, in the brain, with particular emphasis on how altered signaling of these adipokines in obesity may lead to cognitive dysfunction and augmented risk for Alzheimer's disease. A better understanding of adipokine biology in brain disorders may prove of major relevance to diagnostic, prevention and therapy.
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Affiliation(s)
- Leticia Forny-Germano
- Institute of Medical Biochemistry Leopoldo de Meis, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
| | - Fernanda G. De Felice
- Institute of Medical Biochemistry Leopoldo de Meis, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
- Centre for Neuroscience Studies, Department of Psychiatry, Queen’s University, Kingston, ON, Canada
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Hill JW, Elias CF. Neuroanatomical Framework of the Metabolic Control of Reproduction. Physiol Rev 2019; 98:2349-2380. [PMID: 30109817 DOI: 10.1152/physrev.00033.2017] [Citation(s) in RCA: 38] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
A minimum amount of energy is required for basic physiological processes, such as protein biosynthesis, thermoregulation, locomotion, cardiovascular function, and digestion. However, for reproductive function and survival of the species, extra energy stores are necessary. Production of sex hormones and gametes, pubertal development, pregnancy, lactation, and parental care all require energy reserves. Thus the physiological systems that control energy homeostasis and reproductive function coevolved in mammals to support both individual health and species subsistence. In this review, we aim to gather scientific knowledge produced by laboratories around the world on the role of the brain in integrating metabolism and reproduction. We describe essential neuronal networks, highlighting key nodes and potential downstream targets. Novel animal models and genetic tools have produced substantial advances, but critical gaps remain. In times of soaring worldwide obesity and metabolic dysfunction, understanding the mechanisms by which metabolic stress alters reproductive physiology has become crucial for human health.
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Affiliation(s)
- Jennifer W Hill
- Center for Diabetes and Endocrine Research, Departments of Physiology and Pharmacology and of Obstetrics and Gynecology, University of Toledo College of Medicine , Toledo, Ohio ; and Departments of Molecular and Integrative Physiology and of Obstetrics and Gynecology, University of Michigan , Ann Arbor, Michigan
| | - Carol F Elias
- Center for Diabetes and Endocrine Research, Departments of Physiology and Pharmacology and of Obstetrics and Gynecology, University of Toledo College of Medicine , Toledo, Ohio ; and Departments of Molecular and Integrative Physiology and of Obstetrics and Gynecology, University of Michigan , Ann Arbor, Michigan
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37
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Depression and obesity: evidence of shared biological mechanisms. Mol Psychiatry 2019; 24:18-33. [PMID: 29453413 DOI: 10.1038/s41380-018-0017-5] [Citation(s) in RCA: 615] [Impact Index Per Article: 102.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/11/2017] [Revised: 11/13/2017] [Accepted: 12/06/2017] [Indexed: 12/17/2022]
Abstract
Depression and obesity are common conditions with major public health implications that tend to co-occur within individuals. The relationship between these conditions is bidirectional: the presence of one increases the risk for developing the other. It has thus become crucial to gain a better understanding of the mechanisms responsible for the intertwined downward physiological spirals associated with both conditions. The present review focuses specifically on shared biological pathways that may mechanistically explain the depression-obesity link, including genetics, alterations in systems involved in homeostatic adjustments (HPA axis, immuno-inflammatory activation, neuroendocrine regulators of energy metabolism including leptin and insulin, and microbiome) and brain circuitries integrating homeostatic and mood regulatory responses. Furthermore, the review addresses interventional opportunities and questions to be answered by future research that will enable a comprehensive characterization and targeting of the biological links between depression and obesity.
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Agorastos A, Pervanidou P, Chrousos GP, Baker DG. Developmental Trajectories of Early Life Stress and Trauma: A Narrative Review on Neurobiological Aspects Beyond Stress System Dysregulation. Front Psychiatry 2019; 10:118. [PMID: 30914979 PMCID: PMC6421311 DOI: 10.3389/fpsyt.2019.00118] [Citation(s) in RCA: 216] [Impact Index Per Article: 36.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/22/2018] [Accepted: 02/15/2019] [Indexed: 12/21/2022] Open
Abstract
Early life stressors display a high universal prevalence and constitute a major public health problem. Prolonged psychoneurobiological alterations as sequelae of early life stress (ELS) could represent a developmental risk factor and mediate risk for disease, leading to higher physical and mental morbidity rates in later life. ELS could exert a programming effect on sensitive neuronal brain networks related to the stress response during critical periods of development and thus lead to enduring hyper- or hypo-activation of the stress system and altered glucocorticoid signaling. In addition, alterations in emotional and autonomic reactivity, circadian rhythm disruption, functional and structural changes in the brain, as well as immune and metabolic dysregulation have been lately identified as important risk factors for a chronically impaired homeostatic balance after ELS. Furthermore, human genetic background and epigenetic modifications through stress-related gene expression could interact with these alterations and explain inter-individual variation in vulnerability or resilience to stress. This narrative review presents relevant evidence from mainly human research on the ten most acknowledged neurobiological allostatic pathways exerting enduring adverse effects of ELS even decades later (hypothalamic-pituitary-adrenal axis, autonomic nervous system, immune system and inflammation, oxidative stress, cardiovascular system, gut microbiome, sleep and circadian system, genetics, epigenetics, structural, and functional brain correlates). Although most findings back a causal relation between ELS and psychobiological maladjustment in later life, the precise developmental trajectories and their temporal coincidence has not been elucidated as yet. Future studies should prospectively investigate putative mediators and their temporal sequence, while considering the potentially delayed time-frame for their phenotypical expression. Better screening strategies for ELS are needed for a better individual prevention and treatment.
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Affiliation(s)
- Agorastos Agorastos
- II. Department of Psychiatry, Division of Neurosciences, Faculty of Health Sciences, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Panagiota Pervanidou
- Unit of Developmental and Behavioral Pediatrics, First Department of Pediatrics, School of Medicine, Aghia Sophia Children's Hospital, National and Kapodistrian University of Athens, Athens, Greece
| | - George P Chrousos
- Unit of Developmental and Behavioral Pediatrics, First Department of Pediatrics, School of Medicine, Aghia Sophia Children's Hospital, National and Kapodistrian University of Athens, Athens, Greece
| | - Dewleen G Baker
- Department of Psychiatry, University of California, San Diego, La Jolla, CA, United States.,VA Center of Excellence for Stress and Mental Health, San Diego, La Jolla, CA, United States
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Sweatt SK, Gower BA, Chieh AY, Liu Y, Li L. Sleep quality is differentially related to adiposity in adults. Psychoneuroendocrinology 2018; 98:46-51. [PMID: 30098512 PMCID: PMC6204309 DOI: 10.1016/j.psyneuen.2018.07.024] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/08/2018] [Revised: 07/17/2018] [Accepted: 07/24/2018] [Indexed: 02/03/2023]
Abstract
OBJECTIVES Sleep duration is associated with adiposity in adults. Abdominal adiposity specifically is strongly correlated with metabolic alterations, however, the relationships between abdominal adiposity and sleep quality are incompletely understood. The purpose of this study is to test the hypothesis that abdominal adiposity is related to poor sleep quality while total adiposity is not; and to explore whether pathways, including immune system and hypothalamic-pituitary-adrenal axis, link abdominal adiposity to poor sleep quality. METHODS Subjects were 101 men and women aged 38.88 ± 11.96 years with body mass index between 29.35 ± 6.93 kg/m2. Subjective sleep quality was determined by the Pittsburgh Sleep Questionnaire Index (PSQI). Body composition was determined by dual energy X-ray absorptiometry. Saliva and blood samples were collected for assessment of cortisol and markers of inflammation. In a cross-sectional study design, correlation analysis was conducted to determine the relationships between poor sleep quality and adiposity. Participants were stratified based on PSQI score to evaluate differences in main outcomes between subjects with normal (NSQ; PSQI ≤ 5) vs poor sleep quality (PSQ; PSQI > 5). RESULTS Poor sleep quality was related to greater visceral fat (r = 0.26; p < 0.05), but not total fat. The PSQ group had greater visceral fat compared to the NSQ group (1.11 ± 0.83 kg vs 0.79 ± 0.62 kg; p < 0.05), however, there was no difference in total fat mass (33.18 ± 14.21 kg vs 29.39 ± 13.03 kg; p = 0.24). The PSQ group had significantly greater leptin (1.37 ± 0.07 ng/ml vs 1.08 ± 0.08 ng/ml; p < 0.05), but hypothalamic-pituitary-adrenal axis activity did not differ between the PSQ and NSQ groups. CONCLUSIONS Poor sleep quality is associated with greater visceral adiposity and leptin secretion. Further research is needed to probe potential cause and effect relationships among visceral adipose tissue, leptin, and sleep quality.
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Affiliation(s)
- S. Katherine Sweatt
- Department of Psychiatry and Behavioral Neurobiology,
University of Alabama at Birmingham, Birmingham, AL, 35294
| | - Barbara A. Gower
- Department of Nutrition Sciences, University of Alabama at
Birmingham, Birmingham, AL, 35294
| | - Angela Y Chieh
- Department of Psychiatry and Behavioral Neurobiology,
University of Alabama at Birmingham, Birmingham, AL, 35294
| | - Yang Liu
- Department of Psychiatry and Behavioral Neurobiology,
University of Alabama at Birmingham, Birmingham, AL, 35294
| | - Li Li
- Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham, Birmingham, AL, 35294, United States.
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Maurya R, Bhattacharya P, Dey R, Nakhasi HL. Leptin Functions in Infectious Diseases. Front Immunol 2018; 9:2741. [PMID: 30534129 PMCID: PMC6275238 DOI: 10.3389/fimmu.2018.02741] [Citation(s) in RCA: 79] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2018] [Accepted: 11/07/2018] [Indexed: 01/26/2023] Open
Abstract
Leptin, a pleiotropic protein has long been recognized to play an important role in the regulation of energy homeostasis, metabolism, neuroendocrine function, and other physiological functions through its effects on the central nervous system (CNS) and peripheral tissues. Leptin is secreted by adipose tissue and encoded by the obese (ob) gene. Leptin acts as a central mediator which regulates immunity as well as nutrition. Importantly, leptin can modulate both innate and adaptive immune responses. Leptin deficiency/resistance is associated with dysregulation of cytokine production, increased susceptibility toward infectious diseases, autoimmune disorders, malnutrition and inflammatory responses. Malnutrition induces a state of immunodeficiency and an inclination to death from communicable diseases. Infectious diseases are the disease of poor who invariably suffer from malnutrition that could result from reduced serum leptin levels. Thus, leptin has been placed at the center of many interrelated functions in various pathogenic conditions, such as bacterial, viruses and parasitic infections. We review herein, the recent advances on the role of leptin in malnutrition in pathogenesis of infectious diseases with a particular emphasis on parasitic diseases such as Leishmaniasis, Trypanosomiasis, Amoebiasis, and Malaria.
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Affiliation(s)
- Radheshyam Maurya
- Department of Animal Biology, School of Life Science, University of Hyderabad, Hyderabad, India
| | - Parna Bhattacharya
- Division of Emerging and Transfusion Transmitted Diseases, Center for Biologics Evaluation and Research, Food and Drug Administration, Silver Spring, MD, United States
| | - Ranadhir Dey
- Division of Emerging and Transfusion Transmitted Diseases, Center for Biologics Evaluation and Research, Food and Drug Administration, Silver Spring, MD, United States
| | - Hira L. Nakhasi
- Division of Emerging and Transfusion Transmitted Diseases, Center for Biologics Evaluation and Research, Food and Drug Administration, Silver Spring, MD, United States
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Ibars M, Aragonès G, Ardid-Ruiz A, Gibert-Ramos A, Arola-Arnal A, Suárez M, Bladé C. Seasonal consumption of polyphenol-rich fruits affects the hypothalamic leptin signaling system in a photoperiod-dependent mode. Sci Rep 2018; 8:13572. [PMID: 30206280 PMCID: PMC6133929 DOI: 10.1038/s41598-018-31855-y] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2018] [Accepted: 08/24/2018] [Indexed: 12/13/2022] Open
Abstract
Leptin has a central role in the maintenance of energy homeostasis, and its sensitivity is influenced by both the photoperiod and dietary polyphenols. The aim of this study was to investigate the effect of seasonal consumption of polyphenol-rich fruits on the hypothalamic leptin signaling system in non-obese and obese animals placed under different photoperiods. Non-obese and diet-induced obese male Fischer 344 rats were placed under either a short-day (SD) or long-day (LD) photoperiod and were supplemented with either 100 mg/kg of lyophilized red grapes or cherries. In non-obese animals, both fruits reduced energy balance independent of the photoperiod to which they were placed. However, the hypothalamic gene expression of Pomc was significantly up-regulated only in the SD photoperiod. In contrast, in obese animals only cherry significantly decreased the energy balance, although both fruits were able to counteract the diet-induced increase in hypothalamic AgRP mRNA levels when consumed during the SD photoperiod. In conclusion, the consumption of rich-polyphenol fruits may increase leptin sensitivity through the modulation of the hypothalamic leptin signal pathway mainly when consumed in the SD photoperiod. Therefore, fruit seasonality should be considered, as it can influence energy homeostasis and obesity.
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Affiliation(s)
- Maria Ibars
- Universitat Rovira i Virgili, Department of Biochemistry and Biotechnology, Nutrigenomics Research Group, Tarragona, Spain
| | - Gerard Aragonès
- Universitat Rovira i Virgili, Department of Biochemistry and Biotechnology, Nutrigenomics Research Group, Tarragona, Spain.
| | - Andrea Ardid-Ruiz
- Universitat Rovira i Virgili, Department of Biochemistry and Biotechnology, Nutrigenomics Research Group, Tarragona, Spain
| | - Albert Gibert-Ramos
- Universitat Rovira i Virgili, Department of Biochemistry and Biotechnology, Nutrigenomics Research Group, Tarragona, Spain
| | - Anna Arola-Arnal
- Universitat Rovira i Virgili, Department of Biochemistry and Biotechnology, Nutrigenomics Research Group, Tarragona, Spain
| | - Manuel Suárez
- Universitat Rovira i Virgili, Department of Biochemistry and Biotechnology, Nutrigenomics Research Group, Tarragona, Spain
| | - Cinta Bladé
- Universitat Rovira i Virgili, Department of Biochemistry and Biotechnology, Nutrigenomics Research Group, Tarragona, Spain
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SAĞKAN ÖZTÜRK A, ARPACI A. Obezite ve Ghrelin/Leptin İlişkisi. MUSTAFA KEMAL ÜNIVERSITESI TIP DERGISI 2018. [DOI: 10.17944/mkutfd.328412] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
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Grant AD, Wilsterman K, Smarr BL, Kriegsfeld LJ. Evidence for a Coupled Oscillator Model of Endocrine Ultradian Rhythms. J Biol Rhythms 2018; 33:475-496. [PMID: 30132387 DOI: 10.1177/0748730418791423] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
Whereas long-period temporal structures in endocrine dynamics have been well studied, endocrine rhythms on the scale of hours are relatively unexplored. The study of these ultradian rhythms (URs) has remained nascent, in part, because a theoretical framework unifying ultradian patterns across systems has not been established. The present overview proposes a conceptual coupled oscillator network model of URs in which oscillating hormonal outputs, or nodes, are connected by edges representing the strength of node-node coupling. We propose that variable-strength coupling exists both within and across classic hormonal axes. Because coupled oscillators synchronize, such a model implies that changes across hormonal systems could be inferred by surveying accessible nodes in the network. This implication would at once simplify the study of URs and open new avenues of exploration into conditions affecting coupling. In support of this proposed framework, we review mammalian evidence for (1) URs of the gut-brain axis and the hypothalamo-pituitary-thyroid, -adrenal, and -gonadal axes, (2) UR coupling within and across these axes; and (3) the relation of these URs to body temperature. URs across these systems exhibit behavior broadly consistent with a coupled oscillator network, maintaining both consistent URs and coupling within and across axes. This model may aid the exploration of mammalian physiology at high temporal resolution and improve the understanding of endocrine system dynamics within individuals.
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Affiliation(s)
- Azure D Grant
- The Helen Wills Neuroscience Institute, University of California, Berkeley, California
| | - Kathryn Wilsterman
- Department of Integrative Biology, University of California, Berkeley, California
| | - Benjamin L Smarr
- Department of Psychology, University of California, Berkeley, California
| | - Lance J Kriegsfeld
- The Helen Wills Neuroscience Institute, University of California, Berkeley, California.,Department of Psychology, University of California, Berkeley, California
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Mechanick JI, Zhao S, Garvey WT. Leptin, An Adipokine With Central Importance in the Global Obesity Problem. Glob Heart 2017; 13:113-127. [PMID: 29248361 DOI: 10.1016/j.gheart.2017.10.003] [Citation(s) in RCA: 42] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2017] [Accepted: 10/25/2017] [Indexed: 02/08/2023] Open
Abstract
Leptin has central importance in the global obesity and cardiovascular disease problem. Leptin is principally secreted by adipocytes and acts in the hypothalamus to suppress appetite and food intake, increase energy expenditure, and regulate body weight. Based on clinical translation of specific and networked actions, leptin affects the cardiovascular system and may be a marker and driver of cardiometabolic risk factors with interventions that are actionable by cardiologists. Leptin subnetwork analysis demonstrates a statistically significant role for ethnoculturally and socioeconomically appropriate lifestyle intervention in cardiovascular disease. Emergent mechanistic components and potential diagnostic or therapeutic targets include hexokinase 3, urocortins, clusterin, sialic acid-binding immunoglobulin-like lectin 6, C-reactive protein, platelet glycoprotein VI, albumin, pentraxin 3, ghrelin, obestatin prepropeptide, leptin receptor, neuropeptide Y, and corticotropin-releasing factor receptor 1. Emergent associated symptoms include weight change, eating disorders, vascular necrosis, chronic fatigue, and chest pain. Leptin-targeted therapies are reported for lipodystrophy and leptin deficiency, but they are investigational for leptin resistance, obesity, and other chronic diseases.
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Affiliation(s)
- Jeffrey I Mechanick
- Division of Cardiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Division of Endocrinology, Diabetes, and Bone Disease, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
| | - Shan Zhao
- Basepaws Inc., Redondo Beach, CA, USA
| | - W Timothy Garvey
- Department of Nutritional Sciences and Diabetes Research Center, University of Alabama at Birmingham, Birmingham, AL, USA; Geriatric Research Education and Clinical Center, Birmingham Veterans Affairs Medical Center, Birmingham, AL, USA
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Milaneschi Y, Lamers F, Peyrot WJ, Baune BT, Breen G, Dehghan A, Forstner AJ, Grabe HJ, Homuth G, Kan C, Lewis C, Mullins N, Nauck M, Pistis G, Preisig M, Rivera M, Rietschel M, Streit F, Strohmaier J, Teumer A, Van der Auwera S, Wray NR, Boomsma DI, Penninx BWJH. Genetic Association of Major Depression With Atypical Features and Obesity-Related Immunometabolic Dysregulations. JAMA Psychiatry 2017; 74:1214-1225. [PMID: 29049554 PMCID: PMC6396812 DOI: 10.1001/jamapsychiatry.2017.3016] [Citation(s) in RCA: 159] [Impact Index Per Article: 19.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
IMPORTANCE The association between major depressive disorder (MDD) and obesity may stem from shared immunometabolic mechanisms particularly evident in MDD with atypical features, characterized by increased appetite and/or weight (A/W) during an active episode. OBJECTIVE To determine whether subgroups of patients with MDD stratified according to the A/W criterion had a different degree of genetic overlap with obesity-related traits (body mass index [BMI] and levels of C-reactive protein [CRP] and leptin). DESIGN, SETTING, AND PATIENTS This multicenter study assembled genome-wide genotypic and phenotypic measures from 14 data sets of the Psychiatric Genomics Consortium. Data sets were drawn from case-control, cohort, and population-based studies, including 26 628 participants with established psychiatric diagnoses and genome-wide genotype data. Data on BMI were available for 15 237 participants. Data were retrieved and analyzed from September 28, 2015, through May 20, 2017. MAIN OUTCOMES AND MEASURES Lifetime DSM-IV MDD was diagnosed using structured diagnostic instruments. Patients with MDD were stratified into subgroups according to change in the DSM-IV A/W symptoms as decreased or increased. RESULTS Data included 11 837 participants with MDD and 14 791 control individuals, for a total of 26 628 participants (59.1% female and 40.9% male). Among participants with MDD, 5347 (45.2%) were classified in the decreased A/W and 1871 (15.8%) in the increased A/W subgroups. Common genetic variants explained approximately 10% of the heritability in the 2 subgroups. The increased A/W subgroup showed a strong and positive genetic correlation (SE) with BMI (0.53 [0.15]; P = 6.3 × 10-4), whereas the decreased A/W subgroup showed an inverse correlation (-0.28 [0.14]; P = .06). Furthermore, the decreased A/W subgroup had a higher polygenic risk for increased BMI (odds ratio [OR], 1.18; 95% CI, 1.12-1.25; P = 1.6 × 10-10) and levels of CRP (OR, 1.08; 95% CI, 1.02-1.13; P = 7.3 × 10-3) and leptin (OR, 1.09; 95% CI, 1.06-1.12; P = 1.7 × 10-3). CONCLUSIONS AND RELEVANCE The phenotypic associations between atypical depressive symptoms and obesity-related traits may arise from shared pathophysiologic mechanisms in patients with MDD. Development of treatments effectively targeting immunometabolic dysregulations may benefit patients with depression and obesity, both syndromes with important disability.
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Affiliation(s)
- Yuri Milaneschi
- Department of Psychiatry, Amsterdam Public Health and Amsterdam Neuroscience, Vrije Universiteit Medical Center and GGZ inGeest, Amsterdam, the Netherlands
| | - Femke Lamers
- Department of Psychiatry, Amsterdam Public Health and Amsterdam Neuroscience, Vrije Universiteit Medical Center and GGZ inGeest, Amsterdam, the Netherlands
| | - Wouter J. Peyrot
- Department of Psychiatry, Amsterdam Public Health and Amsterdam Neuroscience, Vrije Universiteit Medical Center and GGZ inGeest, Amsterdam, the Netherlands
| | - Bernhard T. Baune
- Discipline of Psychiatry, University of Adelaide, Adelaide, Australia
| | - Gerome Breen
- Medical Research Council Social Genetic and Developmental Psychiatry Centre, King’s College London, London, England,National Institute for Health Research Biomedical Research Centre for Mental Health, King’s College London, London, England
| | - Abbas Dehghan
- Department of Epidemiology and Biostatistics, Imperial College London, London, England
| | - Andreas J. Forstner
- Institute of Human Genetics, University of Bonn, Bonn, Germany,Life Brain Center, Department of Genomics, University of Bonn, Bonn, Germany,Department of Psychiatry, University of Basel, Basel, Switzerland,Human Genomics Research Group, Department of Biomedicine, University of Basel, Basel, Switzerland,Institute of Medical Genetics and Pathology, University Hospital Basel, Basel, Switzerland
| | - Hans J. Grabe
- Department of Psychiatry and Psychotherapy, University Medicine Greifswald, Greifswald, Germany
| | - Georg Homuth
- Interfaculty Institute for Genetics and Functional Genomics, Department of Functional Genomics, University Medicine and Ernst Moritz Arndt University Greifswald, Greifswald, Germany
| | - Carol Kan
- Department of Psychological Medicine, King’s College London, London, England,South London and Maudsley National Health Service Foundation, London, England
| | - Cathryn Lewis
- Medical Research Council Social Genetic and Developmental Psychiatry Centre, King’s College London, London, England
| | - Niamh Mullins
- Medical Research Council Social Genetic and Developmental Psychiatry Centre, King’s College London, London, England
| | - Matthias Nauck
- German Centre for Cardiovascular Research, Partner Site Greifswald, University Medicine, University Medicine Greifswald, Greifswald, Germany,Institute of Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald, Greifswald, Germany
| | - Giorgio Pistis
- Department of Psychiatry, University Hospital of Lausanne, Prilly, Switzerland
| | - Martin Preisig
- Department of Psychiatry, University Hospital of Lausanne, Prilly, Switzerland
| | - Margarita Rivera
- Medical Research Council Social Genetic and Developmental Psychiatry Centre, King’s College London, London, England,Department of Biochemistry and Molecular Biology II, Institute of Neurosciences, Center for Biomedical Research, University of Granada, Granada, Spain
| | - Marcella Rietschel
- Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Fabian Streit
- Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Jana Strohmaier
- Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Alexander Teumer
- Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany
| | - Sandra Van der Auwera
- Department of Psychiatry and Psychotherapy, University Medicine Greifswald, Greifswald, Germany
| | - Naomi R. Wray
- Institute for Molecular Bioscience, University of Queensland, Brisbane, Australia,Queensland Brain Institute, University of Queensland, Brisbane, Australia
| | - Dorret I. Boomsma
- Department of Biological Psychology, VU University Amsterdam, Amsterdam, the Netherlands
| | - Brenda W. J. H. Penninx
- Department of Psychiatry, Amsterdam Public Health and Amsterdam Neuroscience, Vrije Universiteit Medical Center and GGZ inGeest, Amsterdam, the Netherlands
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Milaneschi Y, Lamers F, Bot M, Drent ML, Penninx BWJH. Leptin Dysregulation Is Specifically Associated With Major Depression With Atypical Features: Evidence for a Mechanism Connecting Obesity and Depression. Biol Psychiatry 2017; 81:807-814. [PMID: 26742925 DOI: 10.1016/j.biopsych.2015.10.023] [Citation(s) in RCA: 137] [Impact Index Per Article: 17.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2015] [Revised: 10/27/2015] [Accepted: 10/27/2015] [Indexed: 10/22/2022]
Abstract
BACKGROUND Obesity-related dysregulation of leptin signaling (e.g., hyperleptinemia due to central functional resistance) may affect mood. However, evidence for leptin dysregulation in major depressive disorder (MDD) is conflicting. Inconclusive findings may be attributable to heterogeneity of MDD, aggregating biologically different subtypes. We examined the relationship of leptin with MDD, its common subtypes (typical and atypical), and clinical features. METHODS The sample consisted of participants (aged 18 to 65 years) from the Netherlands Study of Depression and Anxiety with current (n = 1062) or remitted (n = 711) MDD and healthy control subjects (n = 497). Diagnoses of MDD and subtypes were based on DSM-IV symptoms. Additional symptoms were measured with the Inventory of Depressive Symptomatology. Blood levels of leptin and adiposity indexes (body mass index and waist circumference) were assessed. RESULTS As compared to control subjects, higher leptin was associated with the atypical MDD subtype both for remitted (n = 144, odds ratio = 1.53, 95% confidence interval = 1.16-2.03, p = .003) and current (n = 270, odds ratio = 1.90, 95% confidence interval = 1.51-2.93, p = 5.3e-8) cases. This association was stronger for increasing adiposity levels (leptin by body mass index interaction, p < .02), strengthening the hypothesis of the involvement of leptin resistance. No association with leptin was found for overall MDD or the typical subtype. Among currently depressed patients, higher leptin was associated with key symptoms identifying the atypical subtype, such as hyperphagia, increased weight, and leaden paralysis. CONCLUSIONS Leptin dysregulation (resistance) may represent an underlying mechanism connecting obesity and MDD with atypical features. Development of treatment effectively targeting leptin resistance may benefit patients with atypical depression characterized by obesity-related metabolic alterations.
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Affiliation(s)
- Yuri Milaneschi
- Department of Psychiatry, EMGO Institute for Health and Care Research and Neuroscience Campus Amsterdam, VU University Medical Center/GGZ ingest, Amsterdam, The Netherlands.
| | - Femke Lamers
- Department of Psychiatry, EMGO Institute for Health and Care Research and Neuroscience Campus Amsterdam, VU University Medical Center/GGZ ingest, Amsterdam, The Netherlands
| | - Mariska Bot
- Department of Psychiatry, EMGO Institute for Health and Care Research and Neuroscience Campus Amsterdam, VU University Medical Center/GGZ ingest, Amsterdam, The Netherlands
| | - Madeleine L Drent
- Department of Internal Medicine, Endocrine Section, VU University Medical Center, Department of Clinical Neuropsychology, Faculty of Psychology and Education, VU University, Neuroscience Campus Amsterdam, Amsterdam, The Netherlands
| | - Brenda W J H Penninx
- Department of Psychiatry, EMGO Institute for Health and Care Research and Neuroscience Campus Amsterdam, VU University Medical Center/GGZ ingest, Amsterdam, The Netherlands
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48
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Leakey JEA, Seng JE, Barnas CR, Baker VM, Hart RW. A Mechanistic Basis for the Beneficial Effects of Caloric Restriction On Longevity and Disease: Consequences for the Interpretation of Rodent Toxicity Studies. Int J Toxicol 2016. [DOI: 10.1177/109158189801700203] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Caloric restriction in rodents has been repeatedly shown to increase life span while reducing the severity and retarding the onset of both spontaneous and chemically induced neoplasms. These effects of caloric restriction are associated with a spectrum of biochemical and physiological changes that characterize the organism's adaptation to reduced caloric intake and provide the mechanistic basis for caloric restriction's effect on longevity. Here, we review evidence suggesting that the primary adaptation appears to be a rhythmic hypercorticism in the absence of elevated adrenocorticotropin (ACTH) levels. This characteristic hypercorticism evokes a spectrum of responses, including reduced body temperature and increased metabolic efficiency, decreased mitogenic response coupled with increased rates of apoptosis, reduced inflammatory response, reduced oxidative damage to proteins and DNA, reduced reproductive capacity, and altered drug-metabolizing enzyme expression. The net effect of these changes is to (1) decrease growth and metabolism in peripheral tissues to spare energy for central functions, and (2) increase the organism's capacity to withstand stress and chemical toxicity. Thus, caloric restriction research has uncovered an evolutionary mechanism that provides rodents with an adaptive advantage in conditions of fluctuating food supply. During periods of abundance, body growth and fecundity are favored over endurance and longevity. Conversely, during periods of famine, reproductive performance and growth are sacrificed to ensure survival of individuals to breed in better times. This phenomena can be observed in rodent populations that are used in toxicity testing. Improvements over the last 30 years in animal husbandry and nutrition, coupled with selective breeding for growth and fecundity, have resulted in several strains now exhibiting larger animals with reduced survival and increased incidence of background lesions. The mechanistic data from caloric restriction studies suggest that these large animals will also be more susceptible to chemically induced toxicity. This creates a problem in comparing tests performed on animals of different weights and comparing data generated today with the historical database. The rational use of caloric restriction to control body weight to within preset guidelines is a possible way of alleviating this problem.
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Affiliation(s)
- Julian E. A. Leakey
- Office of Research, National Center for Toxicological
Research, Jefferson, Arkansas, USA
| | - John E. Seng
- Office of Research, National Center for Toxicological
Research, Jefferson, Arkansas, USA
| | - Crissy R. Barnas
- Office of Research, National Center for Toxicological
Research, Jefferson, Arkansas, USA, Department of Clinical Pharmacology and Geriatrics,
Northwestern University, 303 E. Superior St., Chicago, IL 60611, USA
| | - Vanessa M. Baker
- Office of Research, National Center for Toxicological
Research, Jefferson, Arkansas, USA
| | - Ronald W. Hart
- Office of Research, National Center for Toxicological
Research, Jefferson, Arkansas, USA
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Kurajoh M, Kadoya M, Morimoto A, Naka M, Miyoshi A, Kanzaki A, Kakutani-Hatayama M, Hamamoto K, Shoji T, Moriwaki Y, Yamamoto T, Inaba M, Namba M, Koyama H. Plasma leptin concentration is associated with fatigue severity in patients with cardiovascular risk factors - HSCAA study. Psychoneuroendocrinology 2016; 74:7-12. [PMID: 27567116 DOI: 10.1016/j.psyneuen.2016.08.016] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/09/2016] [Revised: 07/21/2016] [Accepted: 08/15/2016] [Indexed: 02/06/2023]
Abstract
Fatigue induced by complex dysfunctions of the central nervous system is frequently complained by patients with cardiovascular risk factors. Although leptin is considered to regulate the central nervous system, there are no reports regarding its association with fatigue in those patients. This cross-sectional study included 347 patients with cardiovascular risk factors. Fatigue score and plasma leptin concentration were measured. In addition, abdominal fat accumulation, systemic inflammation, sleep condition, and functions of hypothalamus-pituitary axis and autonomic system were estimated. Plasma leptin concentration (natural logarithm transformed) was significantly and positively (r=0.222, p<0.001) associated with fatigue score, and significantly (p<0.001) higher in the moderately-fatigued group (2.32±0.75ng/ml, mean±SD, n=52) than in the normally-fatigued group (1.85±1.02ng/ml, mean±SD, n=295). Multiple logistic regression analysis showed that plasma leptin concentration was significantly and independently associated with a moderately-fatigued condition independent of other factors, including age, gender, presence of diabetes, hypertension, dyslipidemia, alcohol consumption habit, urinary free cortisol, serum high-sensitive CRP concentration, visceral and subcutaneous fat area, apnea/hypopnea index, sleep efficiency, and heart rate variability. Hyperleptinemia may contribute to fatigue severity in patients with cardiovascular risk factors.
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Affiliation(s)
- Masafumi Kurajoh
- Department of Internal Medicine, Division of Diabetes, Endocrinology and Metabolism, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan; Department of Endocrinology, Metabolism and Molecular Medicine, Osaka City University Graduate School of Medicine, Osaka, Japan.
| | - Manabu Kadoya
- Department of Internal Medicine, Division of Diabetes, Endocrinology and Metabolism, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan
| | - Akiko Morimoto
- Department of Internal Medicine, Division of Diabetes, Endocrinology and Metabolism, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan
| | - Mariko Naka
- Department of Internal Medicine, Division of Diabetes, Endocrinology and Metabolism, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan
| | - Akio Miyoshi
- Department of Internal Medicine, Division of Diabetes, Endocrinology and Metabolism, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan
| | - Akinori Kanzaki
- Department of Internal Medicine, Division of Diabetes, Endocrinology and Metabolism, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan
| | - Miki Kakutani-Hatayama
- Department of Internal Medicine, Division of Diabetes, Endocrinology and Metabolism, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan
| | - Kae Hamamoto
- Department of Internal Medicine, Division of Diabetes, Endocrinology and Metabolism, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan
| | - Takuhito Shoji
- Department of Internal Medicine, Division of Diabetes, Endocrinology and Metabolism, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan
| | - Yuji Moriwaki
- Department of Internal Medicine, Division of Diabetes, Endocrinology and Metabolism, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan
| | - Tetsuya Yamamoto
- Department of Internal Medicine, Division of Diabetes, Endocrinology and Metabolism, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan
| | - Masaaki Inaba
- Department of Endocrinology, Metabolism and Molecular Medicine, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Mitsuyoshi Namba
- Department of Internal Medicine, Division of Diabetes, Endocrinology and Metabolism, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan
| | - Hidenori Koyama
- Department of Internal Medicine, Division of Diabetes, Endocrinology and Metabolism, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan
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Abstract
Leptin, a 167 amino acid adipokine, plays a major role in human energy homeostasis. Its actions are mediated through binding to leptin receptor and activating JAK-STAT3 signal transduction pathway. It is expressed mainly in adipocytes, and its circulating levels reflect the body's energy stores in adipose tissue. Recombinant methionyl human leptin has been FDA approved for patients with generalized non-HIV lipodystrophy and for compassionate use in subjects with congenital leptin deficiency. The purpose of this review is to outline the role of leptin in energy homeostasis, as well as its interaction with other hormones.
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Affiliation(s)
- Georgios A Triantafyllou
- Division of Endocrinology, Diabetes and Metabolism, Department of Internal Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, ST 820, Boston, MA 02215, USA
| | - Stavroula A Paschou
- Division of Endocrinology, Diabetes and Metabolism, Department of Internal Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, ST 820, Boston, MA 02215, USA
| | - Christos S Mantzoros
- Division of Endocrinology, Diabetes and Metabolism, Department of Internal Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, ST 820, Boston, MA 02215, USA.
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