scholarly journals Molecular Insulin Actions Are Sexually Dimorphic in Lipid Metabolism

2021 ◽  
Vol 12 ◽  
Author(s):  
Rosa Isela Ortiz-Huidobro ◽  
Myrian Velasco ◽  
Carlos Larqué ◽  
Rene Escalona ◽  
Marcia Hiriart
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
Sexual Dimorphism ◽  
Energy Homeostasis ◽  
Molecular Mechanisms ◽  
Metabolic Diseases ◽  
Critical Role ◽  
Metabolic Dysfunction ◽  
Anabolic Hormone ◽  
Obesity And Diabetes

The increment in energy-dense food and low physical activity has contributed to the current obesity pandemic, which is more prevalent in women than in men. Insulin is an anabolic hormone that regulates the metabolism of lipids, carbohydrates, and proteins in adipose tissue, liver, and skeletal muscle. During obesity, nutrient storage capacity is dysregulated due to a reduced insulin action on its target organs, producing insulin resistance, an early marker of metabolic dysfunction. Insulin resistance in adipose tissue is central in metabolic diseases due to the critical role that this tissue plays in energy homeostasis. We focused on sexual dimorphism on the molecular mechanisms of insulin actions and their relationship with the physiology and pathophysiology of adipose tissue. Until recently, most of the physiological and pharmacological studies were done in males without considering sexual dimorphism, which is relevant. There is ample clinical and epidemiological evidence of its contribution to the establishment and progression of metabolic diseases. Sexual dimorphism is a critical and often overlooked factor that should be considered in design of sex-targeted therapeutic strategies and public health policies to address obesity and diabetes.

scholarly journals The Role of the Immune System in Obesity and Insulin Resistance

2013 ◽  
Vol 2013 ◽  
pp. 1-9 ◽  
Author(s):  
Payal S. Patel ◽  
Eric D. Buras ◽  
Ashok Balasubramanyam
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
Immune System ◽  
Stress Responses ◽  
Innate Immune System ◽  
Metabolic Diseases ◽  
Innate Immune ◽  
Metabolic Dysfunction ◽  
Adipose Tissue Inflammation ◽  
Tissue Inflammation

The innate immune system provides organisms with rapid and well-coordinated protection from foreign pathogens. However, under certain conditions of metabolic dysfunction, components of the innate immune system may be activated in the absence of external pathogens, leading to pathologic consequences. Indeed, there appears to be an intimate relationship between metabolic diseases and immune dysfunction; for example, macrophages are prime players in the initiation of a chronic inflammatory state in obesity which leads to insulin resistance. In response to increases in free fatty acid release from obese adipose depots, M1-polarized macrophages infiltrate adipose tissues. These M1 macrophages trigger inflammatory signaling and stress responses within cells that signal through JNK or IKKβpathways, leading to insulin resistance. If overnutrition persists, mechanisms that counteract inflammation (such as M2 macrophages and PPAR signaling) are suppressed, and the inflammation becomes chronic. Although macrophages are a principal constituent of obese adipose tissue inflammation, other components of the immune system such as lymphocytes and mast cells also contribute to the inflammatory cascade. Thus it is not merely an increased mass of adipose tissue that directly leads to attenuation of insulin action, but rather adipose tissue inflammation activated by the immune system in obese individuals that leads to insulin resistance.

scholarly journals Effects of ERβ and ERα on OVX-induced changes in adiposity and insulin resistance

2020 ◽  
Vol 245 (1) ◽  
pp. 165-178 ◽  
Author(s):  
Terese M Zidon ◽  
Jaume Padilla ◽  
Kevin L Fritsche ◽  
Rebecca J Welly ◽  
Leighton T McCabe ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Estrogen Receptor ◽  
Adipose Tissue ◽  
Energy Expenditure ◽  
Estrogen Receptor Alpha ◽  
Metabolic Diseases ◽  
Metabolic Effects ◽  
Metabolic Dysfunction ◽  
Gene And Protein Expression ◽  
Induced Changes

Loss of ovarian hormones leads to increased adiposity and insulin resistance (IR), increasing the risk for cardiovascular and metabolic diseases. The purpose of this study was to investigate whether the molecular mechanism behind the adverse systemic and adipose tissue-specific metabolic effects of ovariectomy requires loss of signaling through estrogen receptor alpha (ERα) or estrogen receptor β (ERβ). We examined ovariectomized (OVX) and ovary-intactwild-type (WT), ERα-null (αKO), and ERβ-null (βKO) female mice (age ~49 weeks; n = 7–12/group). All mice were fed a phytoestrogen-free diet (<15 mg/kg) and either remained ovary-intact (INT) or were OVX and followed for 12 weeks. Body composition, energy expenditure, glucose tolerance, and adipose tissue gene and protein expression were analyzed. INT αKO were ~25% fatter with reduced energy expenditure compared to age-matched INT WT controls and βKO mice (all P < 0.001). Following OVX, αKO mice did not increase adiposity or experience a further increase in IR, unlike WT and βKO, suggesting that loss of signaling through ERα mediates OVX-induced metabolic dysfunction. In fact, OVX in αKO mice (i.e., signaling through ERβ in the absence of ERα) resulted in reduced adiposity, adipocyte size, and IR (P < 0.05 for all). βKO mice responded adversely to OVX in terms of increased adiposity and development of IR. Together, these findings challenge the paradigm that ERα mediates metabolic protection over ERβ in all settings. These findings lead us to suggest that, following ovarian hormone loss, ERβ may mediate protective metabolic benefits.

scholarly journals Epigenetic Regulators of White Adipocyte Browning

Epigenomes ◽  
2021 ◽  
Vol 5 (1) ◽  
pp. 3
Author(s):  
Ravikanth Nanduri
Keyword(s):  
Adipose Tissue ◽  
Metabolic Disorders ◽  
Energy Homeostasis ◽  
Molecular Mechanisms ◽  
White Adipocyte ◽  
Primary Function ◽  
Obesity And Diabetes ◽  
Brown Adipose ◽  
Beige Adipocytes ◽  
Epigenetic Regulators

Adipocytes play an essential role in maintaining energy homeostasis in mammals. The primary function of white adipose tissue (WAT) is to store energy; for brown adipose tissue (BAT), primary function is to release fats in the form of heat. Dysfunctional or excess WAT can induce metabolic disorders such as dyslipidemia, obesity, and diabetes. Preadipocytes or adipocytes from WAT possess sufficient plasticity as they can transdifferentiate into brown-like beige adipocytes. Studies in both humans and rodents showed that brown and beige adipocytes could improve metabolic health and protect from metabolic disorders. Brown fat requires activation via exposure to cold or β-adrenergic receptor (β-AR) agonists to protect from hypothermia. Considering the fact that the usage of β-AR agonists is still in question with their associated side effects, selective induction of WAT browning is therapeutically important instead of activating of BAT. Hence, a better understanding of the molecular mechanisms governing white adipocyte browning is vital. At the same time, it is also essential to understand the factors that define white adipocyte identity and inhibit white adipocyte browning. This literature review is a comprehensive and focused update on the epigenetic regulators crucial for differentiation and browning of white adipocytes.

scholarly journals RACK1 is required for adipogenesis

2016 ◽  
Vol 311 (5) ◽  
pp. C831-C836 ◽  
Author(s):  
Qinghua Kong ◽  
Lan Gao ◽  
Yanfen Niu ◽  
Pianchou Gongpan ◽  
Yuhui Xu ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Signaling Pathway ◽  
Energy Homeostasis ◽  
Adipocyte Differentiation ◽  
Metabolic Diseases ◽  
Critical Role ◽  
Adaptor Protein ◽  
Protein Levels ◽  
Ppar Γ ◽  
Intracellular Signal

Adipose tissue plays a critical role in metabolic diseases and the maintenance of energy homeostasis. RACK1 has been identified as an adaptor protein involved in multiple intracellular signal transduction pathways and diseases. However, whether it regulates adipogenesis remains unknown. Here, we reported that RACK1 is expressed in 3T3-L1 cells and murine white adipose tissue and that RACK1 knockdown by shRNA profoundly suppressed adipogenesis by reducing the expression of PPAR-γ and C/EBP-β. Depletion of RACK1 increased β-catenin protein levels and activated Wnt signaling. Furthermore, RACK1 knockdown also suppressed the PI3K-Akt-mTOR-S6K signaling pathway by reducing the PI3K p85α, pAkt T473, and S6K p70. Taken together, these results demonstrate that RACK1 is a novel factor required for adipocyte differentiation by emerging Wnt/β-catenin signaling and PI3K-Akt-mTOR-S6K signaling pathway(s).

scholarly journals Mechanisms for food polyphenols to ameliorate insulin resistance and endothelial dysfunction: therapeutic implications for diabetes and its cardiovascular complications

2013 ◽  
Vol 305 (6) ◽  
pp. E679-E686 ◽  
Author(s):  
Kashif M. Munir ◽  
Sruti Chandrasekaran ◽  
Feng Gao ◽  
Michael J. Quon
Keyword(s):  
Insulin Resistance ◽  
Endothelial Dysfunction ◽  
Functional Foods ◽  
Molecular Mechanisms ◽  
Metabolic Diseases ◽  
Clinical Medicine ◽  
Cardiovascular Complications ◽  
Therapeutic Implications ◽  
Obesity And Diabetes ◽  
Cardiovascular Morbidity And Mortality

The rising epidemic of diabetes is a pressing issue in clinical medicine worldwide from both healthcare and economic perspectives. This is fueled by overwhelming increases in the incidence and prevalence of obesity. Obesity and diabetes are characterized by both insulin resistance and endothelial dysfunction that lead to substantial increases in cardiovascular morbidity and mortality. Reciprocal relationships between insulin resistance and endothelial dysfunction tightly link metabolic diseases including obesity and diabetes with their cardiovascular complications. Therefore, therapeutic approaches that target either insulin resistance or endothelial dysfunction alone are likely to simultaneously improve both metabolic and cardiovascular pathophysiology and disease outcomes. Moreover, combination therapies with agents targeting distinct mechanisms are likely to have additive or synergistic benefits. Conventional therapies for diabetes and its cardiovascular complications that are both safe and effective are insufficient to meet rising demand. Large, robust, epidemiologic studies demonstrate beneficial metabolic and cardiovascular health effects for many functional foods containing various polyphenols. However, precise molecular mechanisms of action for food polyphenols are largely unknown. Moreover, translation of these insights into effective clinical therapies has not been fully realized. Nevertheless, some functional foods are likely sources for safe and effective therapies and preventative strategies for metabolic diseases and their cardiovascular complications. In this review, we emphasize recent progress in elucidating molecular, cellular, and physiological actions of polyphenols from green tea (EGCG), cocoa (ECG), and citrus fruits (hesperedin) that are related to improving metabolic and cardiovascular pathophysiology. We also discuss a rigorous comprehensive approach to studying functional foods that is essential for developing novel, effective, and safe medications derived from functional foods that will complement existing conventional drugs.

scholarly journals Mechanisms in Endocrinology: LOCAL AND SYSTEMIC EFFECTS OF GLUCOCORTICOIDS ON METABOLISM: NEW LESSONS FROM ANIMAL MODELS

2021 ◽  
Author(s):  
Michael Swarbrick ◽  
Hong Zhou ◽  
Markus Seibel
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
Energy Homeostasis ◽  
Metabolic Diseases ◽  
Visceral Obesity ◽  
Metabolic Effects ◽  
Glucocorticoid Treatment ◽  
Brown Adipose ◽  
Nutrient Partitioning ◽  
Brown Adipose Tissue Thermogenesis

Glucocorticoids regulate a remarkable variety of essential functions, including development, immunomodulation, maintenance of circadian rhythm and the response to stress. Glucocorticoids acutely increase energy availability; this is accomplished not only by mobilizing energy stores, but also by diverting energy away from anabolic processes in tissues such as skeletal muscle and bone. While this metabolic shift is advantageous in the short term, prolonged glucocorticoid exposure frequently results in central obesity, insulin resistance, hyperglycaemia, dyslipidaemia, muscle wasting and osteoporosis. Understanding how glucocorticoids affect nutrient partitioning is therefore critical for preventing the side effects of glucocorticoid treatment. Independently of circulating glucocorticoids, intracellular glucocorticoid activity is regulated by the 11β-hydroxysteroid dehydrogenases 1 and 2 (11β-HSD1 and 2), which activate and inactivate glucocorticoids, respectively. Excessive 11β-HSD1 activity, amplifying local glucocorticoid activity in tissues such as adipose tissue and bone may contribute to visceral obesity, insulin resistance and aging-related bone loss in humans. Several recent findings in animals have considerably expanded our understanding of how glucocorticoids exert their dysmetabolic effects. In mice, disrupting glucocorticoid signalling in either adipose tissue or bone produces marked effects on energy homeostasis. Glucocorticoids have also been shown to influence brown adipose tissue thermogenesis (acute activation, chronic suppression), in both rodents and humans. Lastly, recent studies in mice have demonstrated that many dysmetabolic effects of glucocorticoids are sexually dimorphic, although corresponding results in humans are lacking. Together, these studies have illuminated the mechanisms by which glucocorticoids exert their metabolic effects; and have guided us towards more targeted future treatments for metabolic diseases.

The role of adipose tissue senescence in obesity- and ageing-related metabolic disorders

2020 ◽  
Vol 134 (2) ◽  
pp. 315-330 ◽  
Author(s):  
Zhuohao Liu ◽  
Kelvin K.L. Wu ◽  
Xue Jiang ◽  
Aimin Xu ◽  
Kenneth K.Y. Cheng
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
Energy Homeostasis ◽  
Metabolic Diseases ◽  
Cell Types ◽  
Paracrine Effects ◽  
Fat Depots ◽  
Metabolic Functions ◽  
Multiple Cell ◽  
Treatment Of Obesity

Abstract Adipose tissue as the largest energy reservoir and endocrine organ is essential for maintenance of systemic glucose, lipid and energy homeostasis, but these metabolic functions decline with ageing and obesity. Adipose tissue senescence is one of the common features in obesity and ageing. Although cellular senescence is a defensive mechanism preventing tumorigenesis, its occurrence in adipose tissue causatively induces defective adipogenesis, inflammation, aberrant adipocytokines production and insulin resistance, leading to adipose tissue dysfunction. In addition to these paracrine effects, adipose tissue senescence also triggers systemic inflammation and senescence as well as insulin resistance in the distal metabolic organs, resulting in Type 2 diabetes and other premature physiological declines. Multiple cell types including mature adipocytes, immune cells, endothelial cells and progenitor cells gradually senesce at different levels in different fat depots with ageing and obesity, highlighting the heterogeneity and complexity of adipose tissue senescence. In this review, we discuss the causes and consequences of adipose tissue senescence, and the major cell types responsible for adipose tissue senescence in ageing and obesity. In addition, we summarize the pharmacological approaches and lifestyle intervention targeting adipose tissue senescence for the treatment of obesity- and ageing-related metabolic diseases.

scholarly journals Obesity, insulin resistance and comorbidities ? Mechanisms of association

2014 ◽  
Vol 58 (6) ◽  
pp. 600-609 ◽  
Author(s):  
Ana Valeria B. Castro ◽  
Cathryn M. Kolka ◽  
Stella P. Kim ◽  
Richard N. Bergman
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
Molecular Mechanisms ◽  
Metabolic Diseases ◽  
Polycystic Ovary ◽  
Bone Fragility ◽  
The Body ◽  
Ectopic Fat ◽  
Increased Risk ◽  
Fat Liver

Overall excess of fat, usually defined by the body mass index, is associated with metabolic (e.g. glucose intolerance, type 2 diabetes mellitus (T2DM), dyslipidemia) and non-metabolic disorders (e.g. neoplasias, polycystic ovary syndrome, non-alcoholic fat liver disease, glomerulopathy, bone fragility etc.). However, more than its total amount, the distribution of adipose tissue throughout the body is a better predictor of the risk to the development of those disorders. Fat accumulation in the abdominal area and in non-adipose tissue (ectopic fat), for example, is associated with increased risk to develop metabolic and non-metabolic derangements. On the other hand, observations suggest that individuals who present peripheral adiposity, characterized by large hip and thigh circumferences, have better glucose tolerance, reduced incidence of T2DM and of metabolic syndrome. Insulin resistance (IR) is one of the main culprits in the association between obesity, particularly visceral, and metabolic as well as non-metabolic diseases. In this review we will highlight the current pathophysiological and molecular mechanisms possibly involved in the link between increased VAT, ectopic fat, IR and comorbidities. We will also provide some insights in the identification of these abnormalities. Arq Bras Endocrinol Metab. 2014;58(6):600-9

scholarly journals Interorgan Metabolic Crosstalk in Human Insulin Resistance

2018 ◽  
Vol 98 (3) ◽  
pp. 1371-1415 ◽  
Author(s):  
Sofiya Gancheva ◽  
Tomas Jelenik ◽  
Elisa Álvarez-Hernández ◽  
Michael Roden
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Fatty Acids ◽  
Adipose Tissue ◽  
Insulin Sensitivity ◽  
Insulin Action ◽  
Energy Homeostasis ◽  
Metabolic Diseases ◽  
Short Chain Fatty Acids ◽  
Fatty Acid Esters

Excessive energy intake and reduced energy expenditure drive the development of insulin resistance and metabolic diseases such as obesity and type 2 diabetes mellitus. Metabolic signals derived from dietary intake or secreted from adipose tissue, gut, and liver contribute to energy homeostasis. Recent metabolomic studies identified novel metabolites and enlarged our knowledge on classic metabolites. This review summarizes the evidence of their roles as mediators of interorgan crosstalk and regulators of insulin sensitivity and energy metabolism. Circulating lipids such as free fatty acids, acetate, and palmitoleate from adipose tissue and short-chain fatty acids from the gut effectively act on liver and skeletal muscle. Intracellular lipids such as diacylglycerols and sphingolipids can serve as lipotoxins by directly inhibiting insulin action in muscle and liver. In contrast, fatty acid esters of hydroxy fatty acids have been recently shown to exert a series of beneficial effects. Also, ketoacids are gaining interest as potent modulators of insulin action and mitochondrial function. Finally, branched-chain amino acids not only predict metabolic diseases, but also inhibit insulin signaling. Here, we focus on the metabolic crosstalk in humans, which regulates insulin sensitivity and energy homeostasis in the main insulin-sensitive tissues, skeletal muscle, liver, and adipose tissue.

scholarly journals DsbA-L deficiency in T cells promotes diet-induced thermogenesis through suppressing IFN-γ production

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Haiyan Zhou ◽  
Xinyi Peng ◽  
Jie Hu ◽  
Liwen Wang ◽  
Hairong Luo ◽  
...  
Keyword(s):  
T Cells ◽  
Adipose Tissue ◽  
T Cell ◽  
Energy Homeostasis ◽  
Metabolic Diseases ◽  
Therapeutic Potential ◽  
Whole Body ◽  
Brown Adipose ◽  
Ifn Γ ◽  
Diet Induced Thermogenesis

AbstractAdipose tissue-resident T cells have been recognized as a critical regulator of thermogenesis and energy expenditure, yet the underlying mechanisms remain unclear. Here, we show that high-fat diet (HFD) feeding greatly suppresses the expression of disulfide-bond A oxidoreductase-like protein (DsbA-L), a mitochondria-localized chaperone protein, in adipose-resident T cells, which correlates with reduced T cell mitochondrial function. T cell-specific knockout of DsbA-L enhances diet-induced thermogenesis in brown adipose tissue (BAT) and protects mice from HFD-induced obesity, hepatosteatosis, and insulin resistance. Mechanistically, DsbA-L deficiency in T cells reduces IFN-γ production and activates protein kinase A by reducing phosphodiesterase-4D expression, leading to increased BAT thermogenesis. Taken together, our study uncovers a mechanism by which T cells communicate with brown adipocytes to regulate BAT thermogenesis and whole-body energy homeostasis. Our findings highlight a therapeutic potential of targeting T cells for the treatment of over nutrition-induced obesity and its associated metabolic diseases.

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