Serotonin and energy balance: molecular mechanisms and implications for type 2 diabetes

2007 ◽  
Vol 9 (5) ◽  
pp. 1-24 ◽  
Author(s):  
Daniel D. Lam ◽  
Lora K. Heisler
Keyword(s):  
Type 2 Diabetes ◽  
Energy Balance ◽  
Glucose Homeostasis ◽  
Metabolic Regulation ◽  
Energy Homeostasis ◽  
Molecular Mechanisms ◽  
Peripheral Tissues ◽  
Midbrain Raphe Nuclei ◽  
Treatment Of Obesity

The neurotransmitter serotonin is an important regulator of energy balance. In the brain, serotonergic fibres from midbrain raphe nuclei project to key feeding centres, where serotonin acts on specific receptors to modulate the activity of various downstream neuropeptide systems and autonomic pathways and thus affects ingestive behaviour and energy expenditure. Serotonin, released by intestinal enterochromaffin cells, also appears to regulate energy homeostasis through peripheral mechanisms. Serotonergic effects on energy balance lead to secondary effects on glucose homeostasis, based on a well-established link between obesity and insulin resistance. However, serotonergic pathways may also directly affect glucose homeostasis through regulation of autonomic efferents and/or action on peripheral tissues. Several serotonergic compounds have been evaluated for clinical use in the treatment of obesity and type 2 diabetes; results of these trials are discussed here. Finally, future directions in the elucidation of serotonergic metabolic regulation are discussed.

scholarly journals Sex differences in metabolic regulation and diabetes susceptibility

Diabetologia ◽  
2019 ◽  
Vol 63 (3) ◽  
pp. 453-461 ◽  
Author(s):  
Blandine Tramunt ◽  
Sarra Smati ◽  
Naia Grandgeorge ◽  
Françoise Lenfant ◽  
Jean-François Arnal ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Energy Balance ◽  
Pancreatic Beta Cells ◽  
Metabolic Regulation ◽  
Biological Sex ◽  
Type 2 Diabetes Prevention ◽  
Reproductive Life ◽  
Underlying Mechanisms ◽  
Almost All

AbstractGender and biological sex impact the pathogenesis of numerous diseases, including metabolic disorders such as diabetes. In most parts of the world, diabetes is more prevalent in men than in women, especially in middle-aged populations. In line with this, considering almost all animal models, males are more likely to develop obesity, insulin resistance and hyperglycaemia than females in response to nutritional challenges. As summarised in this review, it is now obvious that many aspects of energy balance and glucose metabolism are regulated differently in males and females and influence their predisposition to type 2 diabetes. During their reproductive life, women exhibit specificities in energy partitioning as compared with men, with carbohydrate and lipid utilisation as fuel sources that favour energy storage in subcutaneous adipose tissues and preserve them from visceral and ectopic fat accumulation. Insulin sensitivity is higher in women, who are also characterised by higher capacities for insulin secretion and incretin responses than men; although, these sex advantages all disappear when glucose tolerance deteriorates towards diabetes. Clinical and experimental observations evidence the protective actions of endogenous oestrogens, mainly through oestrogen receptor α activation in various tissues, including the brain, the liver, skeletal muscle, adipose tissue and pancreatic beta cells. However, beside sex steroids, underlying mechanisms need to be further investigated, especially the role of sex chromosomes, fetal/neonatal programming and epigenetic modifications. On the path to precision medicine, further deciphering sex-specific traits in energy balance and glucose homeostasis is indeed a priority topic to optimise individual approaches in type 2 diabetes prevention and treatment.

scholarly journals Lack of adipocyte purinergic P2Y6receptor greatly improves whole body glucose homeostasis

2020 ◽  
Vol 117 (48) ◽  
pp. 30763-30774
Author(s):  
Shanu Jain ◽  
Sai P. Pydi ◽  
Kiran S. Toti ◽  
Bernard Robaye ◽  
Marco Idzko ◽  
...  
Keyword(s):  
Glucose Homeostasis ◽  
Purinergic Receptor ◽  
Whole Body ◽  
Uridine Diphosphate ◽  
Peripheral Tissues ◽  
Diet Induced Obesity ◽  
Enhanced Expression ◽  
Treatment Of Obesity ◽  
White Fat

Uridine diphosphate (UDP)-activated purinergic receptor P2Y6(P2Y6R) plays a crucial role in controlling energy balance through central mechanisms. However, P2Y6R’s roles in peripheral tissues regulating energy and glucose homeostasis remain unexplored. Here, we report the surprising finding that adipocyte-specific deletion of P2Y6R protects mice from diet-induced obesity, improving glucose tolerance and insulin sensitivity with reduced systemic inflammation. These changes were associated with reduced JNK signaling and enhanced expression and activity of PPARα affecting downstream PGC1α levels leading to beiging of white fat. In contrast, P2Y6R deletion in skeletal muscle reduced glucose uptake, resulting in impaired glucose homeostasis. Interestingly, whole body P2Y6R knockout mice showed metabolic improvements similar to those observed with mice lacking P2Y6R only in adipocytes. Our findings provide compelling evidence that P2Y6R antagonists may prove useful for the treatment of obesity and type 2 diabetes.

scholarly journals Sex differences in the effects of androgens acting in the central nervous system on metabolism

2016 ◽  
Vol 18 (4) ◽  
pp. 415-424 ◽  
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Central Nervous System ◽  
Nervous System ◽  
Metabolic Regulation ◽  
Energy Homeostasis ◽  
Sexually Dimorphic ◽  
Metabolic Homeostasis ◽  
The Central Nervous System

One of the most sexually dimorphic aspects of metabolic regulation is the bidirectional modulation of glucose and energy homeostasis by testosterone in males and females. Testosterone deficiency predisposes men to metabolic dysfunction, with excess adiposity, insulin resistance, and type 2 diabetes, whereas androgen excess predisposes women to insulin resistance, adiposity, and type 2 diabetes. This review discusses how testosterone acts in the central nervous system, and especially the hypothalamus, to promote metabolic homeostasis or dysfunction in a sexually dimorphic manner. We compare the organizational actions of testosterone, which program the hypothalamic control of metabolic homeostasis during development, and the activational actions of testosterone, which affect metabolic function after puberty. We also discuss how the metabolic effect of testosterone is centrally mediated via the androgen receptor.

scholarly journals Lack of Adipocyte Purinergic P2Y6 Receptor Greatly Improves Whole Body Glucose Homeostasis

2020 ◽  
Author(s):  
Shanu Jain ◽  
Sai P. Pydi ◽  
Kiran S. Toti ◽  
Bernard Robaye ◽  
Marco Idzko ◽  
...  
Keyword(s):  
Glucose Homeostasis ◽  
Purinergic Receptor ◽  
Whole Body ◽  
Uridine Diphosphate ◽  
Peripheral Tissues ◽  
Diet Induced Obesity ◽  
Enhanced Expression ◽  
Treatment Of Obesity ◽  
White Fat

ABSTRACTUridine diphosphate (UDP)-activated purinergic receptor P2Y6 (P2Y6R) plays a crucial role in controlling energy balance through central mechanisms. However, P2Y6R’s roles in peripheral tissues regulating energy and glucose homeostasis remain unexplored. Here, we report the surprising novel finding that adipocyte-specific deletion of P2Y6R protects mice from diet-induced obesity, improving glucose tolerance and insulin sensitivity with reduced systemic inflammation. These changes were associated with reduced JNK signaling, and enhanced expression and activity of PPARα affecting downstream PGC1α levels leading to beiging of white fat. In contrast, P2Y6R deletion in skeletal muscle reduced glucose uptake resulting in impaired glucose homeostasis. Interestingly, whole body P2Y6R KO mice showed metabolic improvements similar to those observed with mice lacking P2Y6R only in adipocytes. Our findings provide compelling evidence that P2Y6R antagonists may prove useful for the treatment of obesity and type 2 diabetes.

scholarly journals Exocytosis mechanisms underlying insulin release and glucose uptake: conserved roles for Munc18c and syntaxin 4

2010 ◽  
Vol 298 (3) ◽  
pp. R517-R531 ◽  
Author(s):  
Jenna L. Jewell ◽  
Eunjin Oh ◽  
Debbie C. Thurmond
Keyword(s):  
Type 2 Diabetes ◽  
Insulin Secretion ◽  
Glucose Uptake ◽  
Pancreatic Beta Cells ◽  
Insulin Action ◽  
Molecular Mechanisms ◽  
Receptor Protein ◽  
Peripheral Tissues ◽  
Syntaxin 4

Type 2 diabetes has been coined “a two-hit disease,” as it involves specific defects of glucose-stimulated insulin secretion from the pancreatic beta cells in addition to defects in peripheral tissue insulin action required for glucose uptake. Both of these processes, insulin secretion and glucose uptake, are mediated by SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor) protein core complexes composed of syntaxin, SNAP-23/25, and VAMP proteins. The SNARE core complex is regulated by the Sec1/Munc18 (SM) family of proteins, which selectively bind to their cognate syntaxin isoforms with high affinity. The process of insulin secretion uses multiple Munc18-syntaxin isoform pairs, whereas insulin action in the peripheral tissues appears to use only the Munc18c-syntaxin 4 pair. Importantly, recent reports have linked obesity and Type 2 diabetes in humans with changes in protein levels and single nucleotide polymorphisms (SNPs) of Munc18 and syntaxin isoforms relevant to these exocytotic processes, although the molecular mechanisms underlying the observed phenotypes remain incomplete ( 5 , 104 , 144 ). Given the conservation of these proteins in two seemingly disparate processes and the need to design and implement novel and more effective clinical interventions, it will be vitally important to delineate the mechanisms governing these conserved SNARE-mediated exocytosis events. Thus, we provide here an up-to-date historical review of advancements in defining the roles and molecular mechanisms of Munc18-syntaxin complexes in the pathophysiology of Type 2 diabetes.

scholarly journals An Update to the WISP-1/CCN4 Role in Obesity, Insulin Resistance and Diabetes

Medicina ◽  
2021 ◽  
Vol 57 (2) ◽  
pp. 100
Author(s):  
Małgorzata Mirr ◽  
Maciej Owecki
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Adipose Tissue ◽  
Energy Homeostasis ◽  
Peripheral Tissues ◽  
Insulin Resistant ◽  
Highly Active ◽  
Underlying Processes

Insulin resistance refers to the diminished response of peripheral tissues to insulin and is considered the major risk factor for type 2 diabetes. Although many possible mechanisms have been reported to develop insulin resistance, the exact underlying processes remain unclear. In recent years, the role of adipose tissue as a highly active metabolic and endocrine organ, producing proteins called adipokines and their multidirectional activities has gained interest. The physiological effects of adipokines include energy homeostasis and insulin sensitivity regulation. In addition, an excess of adipose tissue is followed by proinflammatory state which results in dysregulation of secreted cytokines contributing to insulin resistance. Wingless-type (Wnt) inducible signalling pathway protein-1 (WISP-1), also known as CCN4, has recently been described as a novel adipokine, whose circulating levels are elevated in obese and insulin resistant individuals. Growing evidence suggests that WISP-1 may participate in the impaired glucose homeostasis. In this review, we characterize WISP-1 and summarize the latest reports on the role of WISP-1 in obesity, insulin resistance and type 2 diabetes.

scholarly journals The Pleiotropic Potential of BDNF beyond Neurons: Implication for a Healthy Mind in a Healthy Body

Life ◽  
2021 ◽  
Vol 11 (11) ◽  
pp. 1256
Author(s):  
Maria Carmela Di Rosa ◽  
Stefania Zimbone ◽  
Miriam Wissam Saab ◽  
Marianna Flora Tomasello
Keyword(s):  
Energy Balance ◽  
Energy Homeostasis ◽  
Molecular Mechanisms ◽  
Cellular Level ◽  
Adaptive Responses ◽  
Peripheral Tissues ◽  
The Central Nervous System ◽  
The Many ◽  
Feeding Control ◽  
Healthy Body

Brain-derived neurotrophic factor (BDNF) represents one of the most widely studied neurotrophins because of the many mechanisms in which it is involved. Among these, a growing body of evidence indicates BDNF as a pleiotropic signaling molecule and unveils non-negligible implications in the regulation of energy balance. BDNF and its receptor are extensively expressed in the hypothalamus, regions where peripheral signals, associated with feeding control and metabolism activation, and are integrated to elaborate anorexigenic and orexigenic effects. Thus, BDNF coordinates adaptive responses to fluctuations in energy intake and expenditure, connecting the central nervous system with peripheral tissues, including muscle, liver, and the adipose tissue in a complex operational network. This review discusses the latest literature dealing with the involvement of BDNF in the maintenance of energy balance. We have focused on the physiological and molecular mechanisms by which BDNF: (I) controls the mitochondrial function and dynamics; (II) influences thermogenesis and tissue differentiation; (III) mediates the effects of exercise on cognitive functions; and (IV) modulates insulin sensitivity and glucose transport at the cellular level. Deepening the understanding of the mechanisms exploited to maintain energy homeostasis will lay the groundwork for the development of novel therapeutical approaches to help people to maintain a healthy mind in a healthy body.

Adipose tissue: an endocrine organ playing a role in metabolic regulation

2016 ◽  
Vol 26 (1) ◽  
Author(s):  
Andrea Booth ◽  
Aaron Magnuson ◽  
Josephine Fouts ◽  
Michelle T. Foster
Keyword(s):  
Type 2 Diabetes ◽  
Adipose Tissue ◽  
Glucose Homeostasis ◽  
Insulin Signaling ◽  
Metabolic Regulation ◽  
Cell Function ◽  
Immune Cell ◽  
Whole Body ◽  
Endocrine Organ

AbstractAdipose tissue is a complex endocrine organ with an intricate role in whole body homeostasis. Beyond storing energy, adipose tissue is fundamental in numerous processes including, but not limited to, metabolism, food intake and immune cell function. Adipokines and cytokines are the signaling factors from adipose tissue. These factors play a role in maintaining health, but are also candidates for pathologies associated with obesity. Indeed excessive adiposity causes dysregulation of these factors which negatively affect health and contribute to numerous obesity-induced co-morbidities. In particular, adipokines are fundamental in regulation of glucose homeostasis and insulin signaling, thus aberrant production of these adipose derived hormones correlates with the development and progression of type 2 diabetes. Therefore, elucidation of adipose regulation is crucial for understanding the pathophysiological basis of obesity and metabolic diseases such as type 2 diabetes. In the present review, we summarize current data on the relation between adipokines and adipose depot derived cytokines in the maintenance of glucose homeostasis. Specifically, physiological and molecular functions of several adipokines are defined with particular focus on interactions within the insulin-signaling pathway and subsequent regulation of glucose uptake in both standard and obesity-induced dysregulated conditions. This same relation will be discussed for cytokines and inflammation as well.

scholarly journals Type 2 Diabetes Mellitus and Cancer: The Role of Pharmacotherapy

2016 ◽  
Vol 34 (35) ◽  
pp. 4261-4269 ◽  
Author(s):  
Gadi Shlomai ◽  
Brian Neel ◽  
Derek LeRoith ◽  
Emily Jane Gallagher
Keyword(s):  
Diabetes Mellitus ◽  
Type 2 Diabetes ◽  
Type 2 Diabetes Mellitus ◽  
Glucose Homeostasis ◽  
Cancer Incidence ◽  
Metabolic Effects ◽  
Peripheral Tissues ◽  
Cancer Data ◽  
Incidence And Mortality

Purpose Type 2 diabetes mellitus (T2DM) is becoming increasingly prevalent worldwide. Epidemiologic data suggest that T2DM is associated with an increased incidence and mortality from many cancers. The purpose of this review is to discuss the links between diabetes and cancer, the effects of various antidiabetic medications on cancer incidence and mortality, and the effects of anticancer therapies on diabetes. Design This study is a review of preclinical and clinical data regarding the effects of antidiabetic medications on cancer incidence and mortality and the effects of anticancer therapies on glucose homeostasis. Results T2DM is associated with an increased risk and greater mortality from many cancer types. Metformin use has been associated with a decrease in cancer incidence and mortality, and there are many ongoing randomized trials investigating the effects of metformin on cancer-related outcomes. However, data regarding the association of other antidiabetes medications with cancer incidence and mortality are conflicting. Glucocorticoids, hormone-based therapies, inhibitors that target the phosphatidylinositol 3-kinase-Akt-mammalian target of rapamycin pathway, and insulin-like growth factor 1 receptor–targeted therapy have been associated with high rates of hyperglycemia. These agents mediate their deleterious metabolic effects by reducing insulin secretion and increasing insulin resistance in peripheral tissues. Conclusion Studies must be performed to optimize cancer screening strategies in individuals with T2DM. A greater understanding of the mechanisms that link diabetes and cancer are needed to identify targets for therapy in individuals with diabetes who develop cancer. Data from clinical studies are needed to further elucidate the effects of antidiabetic medications on cancer incidence and progression. As several anticancer therapies alter glucose homeostasis, physicians need to be aware of these potential effects. Careful patient screening and monitoring during treatment with these agents is necessary.

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