scholarly journals Update on FXR Biology: Promising Therapeutic Target?

2018 ◽  
Vol 19 (7) ◽  
pp. 2069 ◽  
Author(s):  
Chang Han
Keyword(s):  
Therapeutic Target ◽  
Energy Homeostasis ◽  
Metabolic Diseases ◽  
Current Knowledge ◽  
Farnesoid X Receptor ◽  
Metabolic Effects ◽  
Metabolic Dysfunction ◽  
Energy Status ◽  
Safety Issues ◽  
Attractive Therapeutic Target

Farnesoid X receptor (FXR), a metabolic nuclear receptor, plays critical roles in the maintenance of systemic energy homeostasis and the integrity of many organs, including liver and intestine. It regulates bile acid, lipid, and glucose metabolism, and contributes to inter-organ communication, in particular the enterohepatic signaling pathway, through bile acids and fibroblast growth factor-15/19 (FGF-15/19). The metabolic effects of FXR are also involved in gut microbiota. In addition, FXR has various functions in the kidney, adipose tissue, pancreas, cardiovascular system, and tumorigenesis. Consequently, the deregulation of FXR may lead to abnormalities of specific organs and metabolic dysfunction, allowing the protein as an attractive therapeutic target for the management of liver and/or metabolic diseases. Indeed, many FXR agonists have been being developed and are under pre-clinical and clinical investigations. Although obeticholic acid (OCA) is one of the promising candidates, significant safety issues have remained. The effects of FXR modulation might be multifaceted according to tissue specificity, disease type, and/or energy status, suggesting the careful use of FXR agonists. This review summarizes the current knowledge of systemic FXR biology in various organs and the gut–liver axis, particularly regarding the recent advancement in these fields, and also provides pharmacological aspects of FXR modulation for rational therapeutic strategies and novel drug development.

Glucocorticoid hormones and energy homeostasis

2014 ◽  
Vol 19 (2) ◽  
Author(s):  
Roldan M. de Guia ◽  
Adam J. Rose ◽  
Stephan Herzig
Keyword(s):  
Energy Homeostasis ◽  
Target Genes ◽  
Metabolic Diseases ◽  
Current Knowledge ◽  
Metabolic Dysfunction ◽  
Endocrine Control ◽  
Regulatory Pathways ◽  
Glucose And Lipid Metabolism ◽  
Steroid Binding

AbstractGlucocorticoids (GC) and their cognate intracellular receptor, the glucocorticoid receptor (GR), have been characterised as critical checkpoints in the endocrine control of energy homeostasis in mammals. Indeed, aberrant GC action has been linked to a variety of severe metabolic diseases, including obesity, insulin resistance and type 2 diabetes. As a steroid-binding member of the nuclear receptor superfamily of transcription factors, the GR translocates into the cell nucleus upon GC binding where it serves as a transcriptional regulator of distinct GC-responsive target genes that are – in many cases – associated with glucose and lipid regulatory pathways and thereby intricately control both physiological and pathophysiological systemic energy homeostasis. Here, we summarize the current knowledge of GC/GR function in energy metabolism and systemic metabolic dysfunction, particularly focusing on glucose and lipid metabolism.

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 Bile Acids, FXR, and Metabolic Effects of Bariatric Surgery

2016 ◽  
Vol 2016 ◽  
pp. 1-8 ◽  
Author(s):  
Olivier F. Noel ◽  
Christopher D. Still ◽  
George Argyropoulos ◽  
Michael Edwards ◽  
Glenn S. Gerhard
Keyword(s):  
Bariatric Surgery ◽  
Lipid Metabolism ◽  
Bile Acids ◽  
Metabolic Diseases ◽  
Overweight And Obesity ◽  
Farnesoid X Receptor ◽  
Metabolic Effects ◽  
The Novel ◽  
Treatment Of Obesity ◽  
Lipid Metabolism Genes

Overweight and obesity represent major risk factors for diabetes and related metabolic diseases. Obesity is associated with a chronic and progressive inflammatory response leading to the development of insulin resistance and type 2 diabetes (T2D) mellitus, although the precise mechanism mediating this inflammatory process remains poorly understood. The most effective intervention for the treatment of obesity, bariatric surgery, leads to glucose normalization and remission of T2D. Recent work in both clinical studies and animal models supports bile acids (BAs) as key mediators of these effects. BAs are involved in lipid and glucose homeostasis primarily via the farnesoid X receptor (FXR) transcription factor. BAs are also involved in regulating genes involved in inflammation, obesity, and lipid metabolism. Here, we review the novel role of BAs in bariatric surgery and the intersection between BAs and immune, obesity, weight loss, and lipid metabolism genes.

scholarly journals TFEB drives PGC-1α expression in adipocytes to protect against diet-induced metabolic dysfunction

2019 ◽  
Vol 12 (606) ◽  
pp. eaau2281 ◽  
Author(s):  
Trent D. Evans ◽  
Xiangyu Zhang ◽  
Se-Jin Jeong ◽  
Anyuan He ◽  
Eric Song ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Metabolic Diseases ◽  
Therapeutic Potential ◽  
Metabolic Effects ◽  
Metabolic Dysfunction ◽  
Helix Loop Helix ◽  
Downstream Effects ◽  
Brown Adipose ◽  
Tissue Browning

TFEB is a basic helix-loop-helix transcription factor that confers protection against metabolic diseases such as atherosclerosis by targeting a network of genes involved in autophagy-lysosomal biogenesis and lipid catabolism. In this study, we sought to characterize the role of TFEB in adipocyte and adipose tissue physiology and evaluate the therapeutic potential of adipocyte-specific TFEB overexpression in obesity. We demonstrated that mice with adipocyte-specific TFEB overexpression (Adipo-TFEB) were protected from diet-induced obesity, insulin resistance, and metabolic sequelae. Adipo-TFEB mice were lean primarily through increased metabolic rate, suggesting a role for adipose tissue browning and enhanced nonshivering thermogenesis in fat. Transcriptional characterization revealed that TFEB targeted genes involved in adipose tissue browning rather than those involved in autophagy. One such gene encoded PGC-1α, an established target of TFEB that promotes adipocyte browning. To dissect the role of PGC-1α in mediating the downstream effects of TFEB overexpression, we generated mice with adipocyte-specific PGC-1α deficiency and TFEB overexpression. Without PGC-1α, the ability of TFEB overexpression to brown adipose tissue and to elicit beneficial metabolic effects was blunted. Overall, these data implicate TFEB as a PGC-1α–dependent regulator of adipocyte browning and suggest its therapeutic potential in treating metabolic disease.

scholarly journals The autophagy inducer spermidine protects against metabolic dysfunction during overnutrition

2021 ◽  
Author(s):  
Chen-Yu Liao ◽  
Oona M P Kummert ◽  
Amanda M Bair ◽  
Nora Alavi ◽  
Josef Alavi ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Visceral Fat ◽  
Energy Homeostasis ◽  
Subcutaneous Fat ◽  
Metabolic Effects ◽  
Daily Injection ◽  
Metabolic Dysfunction ◽  
Diet Induced Obesity ◽  
Old Mice ◽  
Fgf21 Expression

Abstract Autophagy, a process catabolizing intracellular components to maintain energy homeostasis, impacts aging and metabolism. Spermidine, a natural polyamine and autophagy activator, extends lifespan across a variety of species, including mice. In addition to protecting cardiac and liver tissue, spermidine also affects adipose tissue through unexplored mechanisms. Here, we examined spermidine in the links between autophagy and systemic metabolism. Consistently, daily injection of spermidine delivered even at late life is sufficient to cause a trend in lifespan extension in wild type mice. We further found that spermidine has minimal metabolic effects in young and old mice under normal nutrition. However, spermidine counteracts HFD (high-fat diet)-induced obesity by increasing lipolysis in visceral fat. Mechanistically, spermidine increases the hepatokine FGF21 expression in liver without reducing food intake. Spermidine also modulates FGF21 in adipose tissues, elevating FGF21 expression in subcutaneous fat, but reducing it in visceral fat. Despite this, FGF21 is not required for spermidine action, since Fgf21  -/- mice were still protected from HFD. Furthermore, the enhanced lipolysis by spermidine was also independent of autophagy in adipose tissue, given that adipose-specific autophagy deficient (Beclin-1  flox/+  Fabp4-cre) mice remained spermidine-responsive under HFD. Our results suggest that the metabolic effects of spermidine occurs through systemic changes in metabolism, involving multiple mechanistic pathways.

scholarly journals Bone Cell Bioenergetics and Skeletal Energy Homeostasis

2017 ◽  
Vol 97 (2) ◽  
pp. 667-698 ◽  
Author(s):  
Ryan C. Riddle ◽  
Thomas L. Clemens
Keyword(s):  
Energy Homeostasis ◽  
Metabolic Diseases ◽  
Bone Cells ◽  
Bone Cell ◽  
Intermediary Metabolism ◽  
Energy Status ◽  
Health And Disease ◽  
Rising Incidence ◽  
Metabolic Properties

The rising incidence of metabolic diseases worldwide has prompted renewed interest in the study of intermediary metabolism and cellular bioenergetics. The application of modern biochemical methods for quantitating fuel substrate metabolism with advanced mouse genetic approaches has greatly increased understanding of the mechanisms that integrate energy metabolism in the whole organism. Examination of the intermediary metabolism of skeletal cells has been sparked by a series of unanticipated observations in genetically modified mice that suggest the existence of novel endocrine pathways through which bone cells communicate their energy status to other centers of metabolic control. The recognition of this expanded role of the skeleton has in turn led to new lines of inquiry directed at defining the fuel requirements and bioenergetic properties of bone cells. This article provides a comprehensive review of historical and contemporary studies on the metabolic properties of bone cells and the mechanisms that control energy substrate utilization and bioenergetics. Special attention is devoted to identifying gaps in our current understanding of this new area of skeletal biology that will require additional research to better define the physiological significance of skeletal cell bioenergetics in human health and disease.

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 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.

scholarly journals Epigenetics and life-long consequences of an adverse nutritional and diabetic intrauterine environment

Reproduction ◽  
2014 ◽  
Vol 148 (6) ◽  
pp. R111-R120 ◽  
Author(s):  
Nady El Hajj ◽  
Eberhard Schneider ◽  
Harald Lehnen ◽  
Thomas Haaf
Keyword(s):  
Metabolic Disease ◽  
Gestational Diabetes ◽  
Energy Homeostasis ◽  
Complex Disease ◽  
Maternal Obesity ◽  
Metabolic Diseases ◽  
Current Knowledge ◽  
Time Windows ◽  
Intrauterine Environment ◽  
Fetal Overnutrition

The phenomenon that adverse environmental exposures in early life are associated with increased susceptibilities for many adult, particularly metabolic diseases, is now referred to as ‘developmental origins of health and disease (DOHAD)’ or ‘Barker’ hypothesis. Fetal overnutrition and undernutrition have similar long-lasting effects on the setting of the neuroendocrine control systems, energy homeostasis, and metabolism, leading to life-long increased morbidity. There are sensitive time windows during early development, where environmental cues can program persistent epigenetic modifications which are generally assumed to mediate these gene–environment interactions. Most of our current knowledge on fetal programing comes from animal models and epidemiological studies in humans, in particular the Dutch famine birth cohort. In industrialized countries, there is more concern about adverse long-term consequences of fetal overnutrition, i.e. by exposure to gestational diabetes mellitus and/or maternal obesity which affect 10–20% of pregnancies. Epigenetic changes due to maternal diabetes/obesity may predispose the offspring to develop metabolic disease later in life and, thus, transmit the adverse environmental exposure to the next generation. This vicious cycle could contribute significantly to the worldwide metabolic disease epidemics. In this review article, we focus on the epigenetics of an adverse intrauterine environment, in particular gestational diabetes, and its implications for the prevention of complex disease.

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