Insulin sensing by astrocytes is critical for normal thermogenesis and body temperature regulation

The important role of astrocytes in the central control of energy balance and glucose homeostasis has recently been recognized. Changes in thermoregulation can lead to metabolic dysregulation, but the role of astrocytes in this process is not yet clear. Therefore, we generated mice congenitally lacking insulin receptors (Ir) in astrocytes (IrKOGFAP mice) to investigate the involvement of astrocyte insulin signaling. IrKOGFAP mice displayed significantly lower energy expenditure and a strikingly lower basal and fasting body temperature. When exposed to cold, however, they were able to mount a thermogenic response. IrKOGFAP mice displayed sex differences in metabolic function and thermogenesis that may contribute to the development of obesity and type II diabetes as early as 2 months of age. While brown adipose tissue exhibited higher adipocyte size in both sexes, more apoptosis was seen in IrKOGFAP males. Less innervation and lower BAR3 expression levels were also observed in IrKOGFAP brown adipose tissue. These effects have not been reported in models of astrocyte Ir deletion in adulthood. In contrast, body weight and glucose regulatory defects phenocopied such models. These findings identify a novel role for astrocyte insulin signaling in the development of normal body temperature control and sympathetic activation of BAT. Targeting insulin signaling in astrocytes has the potential to serve as a novel target for increasing energy expenditure.

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SAT-LB107 Insulin Sensing by Astrocytes Is Critical for Normal Thermogenesis and Body Temperature Regulation

Journal of the Endocrine Society ◽

10.1210/jendso/bvaa046.2300 ◽

2020 ◽

Vol 4 (Supplement_1) ◽

Author(s):

Jennifer Wootton Hill ◽

Iyad H Manaserh

Keyword(s):

Body Temperature ◽

Energy Expenditure ◽

Insulin Signaling ◽

Insulin Receptors ◽

Normal Body Temperature ◽

Metabolic Dysregulation ◽

Brown Adipose ◽

Novel Target ◽

Thermogenic Response

Abstract The important role of astrocytes in the central control of energy balance and glucose homeostasis has only recently been recognized. Changes in thermoregulation can lead to metabolic dysregulation, but the role of astrocytes in this process is not yet clear. Therefore, we generated mice congenitally lacking insulin receptors (IR) in astrocytes (IRKOGFAP mice) to investigate the involvement of astrocyte insulin signaling. IRKOGFAP mice displayed a significant decrease in energy expenditure and a striking decrease in basal and fasting body temperature. When exposed to cold, however, they were able to mount a thermogenic response. Brown adipose tissue in IRKOGFAP mice exhibited increased adipocyte size, more apoptosis, loss of innervation, and decreased βAR3 expression levels. These findings identify a novel role for astrocyte insulin signaling in the development of normal body temperature control and sympathetic activation of BAT. Targeting insulin signaling in astrocytes has the potential to serve as a novel target for increasing energy expenditure.

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Deregulation of PP2A-Akt Interaction Contributes to Sucrose Non-Fermenting Related Kinase (SNRK) Deficiency Induced Insulin Resistance in Adipose Tissue (P21-071-19)

Current Developments in Nutrition ◽

10.1093/cdn/nzz041.p21-071-19 ◽

2019 ◽

Vol 3 (Supplement_1) ◽

Cited By ~ 1

Author(s):

Jie Li ◽

Ran An ◽

Simin Liu ◽

Haiyan Xu

Keyword(s):

Insulin Resistance ◽

Adipose Tissue ◽

Brown Adipose Tissue ◽

Glucose Homeostasis ◽

Insulin Signaling ◽

Brown Adipocytes ◽

Brown Adipose ◽

Knockout Model ◽

Potential Substrate

Abstract Objectives Sucrose Non-Fermenting Related Kinase (SNRK), a serine/threonine kinase, is a novel member of the AMPK/SNF1 family. We previously reported that adipose specific SNRK deficiency induced systemic inflammation and insulin resistance. In this study, we aimed to dissect the role of SNRK in white versus brown adipose tissue in insulin signaling and glucose homeostasis. Methods The SNRKloxp/loxp mice were mated with adiponectin-Cre (A-Cre) transgenic mice to generate the adipose tissue specific knockout model (SNRK−/−, A-Cre), and with UCP1-Cre (U-Cre) mice to generate the brown adipose tissue (BAT) specific knockout model (SNRK−/−, U-Cre). RNA sequencing and phosphoproteomics analysis were applied to identify the signaling pathways affected by SNRK deficiency and the potential substrate of SNRK. Results SNRK deletion exclusively in BAT is sufficient to impair insulin signaling and glucose uptake without inducing local and systemic inflammation. Phosphoproteomic study identified PPP2R5D as the potential substrate of SNRK that regulates insulin signaling through controlling PP2A activity. Dephosphorylated PPP2R5D promotes constitutive assembly of PP2A-Akt complex in SNRK deficient primary brown adipocytes and BAT, therefore reduces insulin stimulated Akt phosphorylation and subsequent glucose uptake. RNA sequencing data provided further evidence to show that the PI3K/AKT signaling pathway is suppressed by SNRK deletion in primary brown adipocytes. Conclusions Insulin resistance in BAT alone is not sufficient to impact whole body glucose homeostasis, indicating that the role of SNRK in WAT and inflammation might be critical for observed systemic insulin resistance in SNRK−/−, A-Cre mice. Funding Sources National Institute of Diabetes and Digestive and Kidney Diseases (R01 DK103699).

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Obesity: The role of desynchronosis and genetic factors in mechanisms of its development

Regulatory Mechanisms in Biosystems ◽

10.15421/021705 ◽

2017 ◽

Vol 8 (1) ◽

pp. 23-29

Author(s):

M. O. Ryznychuk ◽

V. P. Pishak

Keyword(s):

Insulin Resistance ◽

Adipose Tissue ◽

Insulin Signaling ◽

Genetic Factors ◽

Hormone Secretion ◽

Insulin Receptors ◽

Secretory Activity ◽

Membrane Receptors ◽

Brown Adipose

The article highlights the role of desynchronosis and certain genetic factors in the development of obesity. Some pathogenetic links of obesity and the influence of melatonin on them are analyzed.Desynchronosis is one of the causes of obesity as a result of dysregulatory changes in the chronoperiodic system – between suprachiasmatic nuclei of the hypothalamus and secretory activity of the pineal gland.In obesity there are some changes in circadian patterns of important physiological parameters. These include acrophases of blood pressure; rhythm of hormone secretion, including insulin; electrolytes; sleep-wake cycle displaced for a period of a day, which is a deviation from the normal course. Phase discrepancies of established circadian oscillations of physiological processes arise. Preconditions of fat metabolism imbalance, particularly visfatin, apelin and vaspin – components of atherosclerotic lesions, gradually emerge.There is abundant evidence for close relationships between metabolism and circadian mechanisms. It is proved, that there is a strong direct impact of endogenous circadian rhythms on the metabolic pathways that do not depend on food intake or sleep. A potential low molecular weight of biomarkers of human circadian phases has been identified. A number of key metabolic enzymes in tissues such as the liver, adipose tissue or the pancreas are chronodependent. Desynchronosis phenomena caused by genetic or environmental factors can lead to serious metabolic disorders, including obesity, insulin resistance and metabolic syndrome.Genesis of pineal removal-induced insulin resistance and reduced glucose tolerance in cells is related to the consequences of melatonin absence, which leads to abnormalities in insulin signaling pathways and reduced GLUT4 gene expression and protein content.Insulin-sensitive tissues (white and brown adipose tissue, skeletal and heart muscles) after pineal removal are characterized by a significant reduction of GLUT4 mRNA and the content of microsomal and membrane proteins, which are compensated during treatment by melatonin. Functional synergy exists between melatonin and insulin. Melatonin is able through the membrane receptors MT1 to cause rapid tyrosine phosphorylation, activate tyrosine kinase of beta subunits of insulin receptors and mobilize several intracellular stages of insulin-signaling pathway transduction.Thus, the protective effect of melatonin in cases of disturbance to the carbohydrate metabolism is manifested in the formation of circadian periodicity by modulating the expression of time genes.

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SUN-590 27-Hydroxycholesterol Triggers the Whitening of Brown Adipose Tissue

Journal of the Endocrine Society ◽

10.1210/jendso/bvaa046.1089 ◽

2020 ◽

Vol 4 (Supplement_1) ◽

Author(s):

Arvand Asghari ◽

Linh Bui ◽

Robert Stephen ◽

Michihisa Umetani

Keyword(s):

Estrogen Receptor ◽

Adipose Tissue ◽

Energy Expenditure ◽

Brown Adipose Tissue ◽

White Adipose Tissue ◽

Vehicle Control ◽

The Body ◽

Wild Type ◽

Brown Adipose

Abstract 27-Hydroxycholesterol (27HC) is the most abundant oxysterol in circulation and metabolized by a P450 enzyme CYP7B1. Its levels closely correspond to those of cholesterol in the body. In addition, previously it was found that 27HC is an endogenous selective estrogen receptor modulator (SERM), which links cholesterol metabolism to estrogen receptor actions (1). Brown adipose tissue (BAT) is the primary source of energy expenditure and energy homeostasis, as well as body temperature maintenance. While previously it was believed that BAT activity is limited to neonates and young children, it is now recognized that BAT is also active in adult humans and its function is impaired by metabolic diseases such as obesity. BAT is also a secretory organ and produces brown adipokines, although the exact function of BAT and adipokines from this tissue in obesity has not been completely understood. Recently, it was reported that 27HC plays an important role in obesity and augments body weight gain in response to a high fat, high cholesterol (HFHC) diet by increasing pre-adipocyte population in the white adipose tissue. 27HC mimics the effects by HFHC diet-feeding on white adipose tissue, such as promoting the inflammation and macrophage infiltration (2). In this study, we explored the effect of 27HC on BAT morphology and function. First, we compared the morphology of BAT from wild-type mice and Cyp7b1-/- mice that have elevated levels of 27HC using H&E staining. Interestingly, brown adipocytes from Cyp7b1-/- mice were larger in cell size than those from wild-type mice, and the cells were mostly unilocular compared to the multilocular cells from wild-type mice, indicating the transition toward a “whitening” phenotype. Next, We treated mice fed a normal chow or a HFHC diet with 27HC or vehicle control for 8 weeks to examine the direct effect by 27HC on BAT. Similar to the phenotype in Cyp7b1-/-mice, 27HC increased the “whitening” of BAT regardless of the diet. We also determined the gene expression of brown adipocyte markers such as UCP1, PGC1a, and DIO2, and found that 27HC significantly decreased the expression of the BAT markers regardless of the diet, confirming the “whitening” observed in the morphology. Moreover, the energy expenditure in mice treated with 27HC was decreased compared to the vehicle control on a HFHC diet, suggesting that 27HC also alters BAT function. These results show that 27HC causes the whitening of BAT, and shed light on the important role of 27HC in brown adipose tissue function. Future experiments will be warranted toward further understanding of the role of 27HC in BAT function. Reference:(1) Umetani, Michihisa, et al. Nature medicine 13.10 (2007): 1185. (2) Asghari, Arvand, et al. Endocrinology 160.10 (2019): 2485-2494.

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Effects of Caffeine on Brown Adipose Tissue Thermogenesis and Metabolic Homeostasis: A Review

Frontiers in Neuroscience ◽

10.3389/fnins.2021.621356 ◽

2021 ◽

Vol 15 ◽

Author(s):

Lachlan Van Schaik ◽

Christine Kettle ◽

Rodney Green ◽

Helen R. Irving ◽

Joseph A. Rathner

Keyword(s):

Adipose Tissue ◽

Energy Expenditure ◽

Brown Adipose Tissue ◽

Energy Utilization ◽

Therapeutic Effects ◽

Exciting Field ◽

Brown Adipose ◽

The Impact

The impact of brown adipose tissue (BAT) metabolism on understanding energy balance in humans is a relatively new and exciting field of research. The pathogenesis of obesity can be largely explained by an imbalance between caloric intake and energy expenditure, but the underlying mechanisms are far more complex. Traditional non-selective sympathetic activators have been used to artificially elevate energy utilization, or suppress appetite, however undesirable side effects are apparent with the use of these pharmacological interventions. Understanding the role of BAT, in relation to human energy homeostasis has the potential to dramatically offset the energy imbalance associated with obesity. This review discusses paradoxical effects of caffeine on peripheral adenosine receptors and the possible role of adenosine in increasing metabolism is highlighted, with consideration to the potential of central rather than peripheral mechanisms for caffeine mediated BAT thermogenesis and energy expenditure. Research on the complex physiology of adipose tissue, the embryonic lineage and function of the different types of adipocytes is summarized. In addition, the effect of BAT on overall human metabolism and the extent of the associated increase in energy expenditure are discussed. The controversy surrounding the primary β-adrenoceptor involved in human BAT activation is examined, and suggestions as to the lack of translational findings from animal to human physiology and human in vitro to in vivo models are provided. This review compares and distinguishes human and rodent BAT effects, thus developing an understanding of human BAT thermogenesis to aid lifestyle interventions targeting obesity and metabolic syndrome. The focus of this review is on the effect of BAT thermogenesis on overall metabolism, and the potential therapeutic effects of caffeine in increasing metabolism via its effects on BAT.

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Adipose tissue insulin resistance due to loss of PI3K p110α leads to decreased energy expenditure and obesity

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00625.2013 ◽

2014 ◽

Vol 306 (10) ◽

pp. E1205-E1216 ◽

Cited By ~ 27

Author(s):

Victoria L. B. Nelson ◽

Ya-Ping Jiang ◽

Kathleen G. Dickman ◽

Lisa M. Ballou ◽

Richard Z. Lin

Keyword(s):

Insulin Resistance ◽

Adipose Tissue ◽

Energy Expenditure ◽

Brown Adipose Tissue ◽

Insulin Signaling ◽

Uncoupling Protein ◽

Critical Role ◽

Liver Steatosis ◽

Cellular Respiration ◽

Brown Adipose

Adipose tissue is a highly insulin-responsive organ that contributes to metabolic regulation. Insulin resistance in the adipose tissue affects systemic lipid and glucose homeostasis. Phosphoinositide 3-kinase (PI3K) mediates downstream insulin signaling in adipose tissue, but its physiological role in vivo remains unclear. Using Cre recombinase driven by the aP2 promoter, we created mice that lack the class 1A PI3K catalytic subunit p110α or p110β specifically in the white and brown adipose tissue. The loss of p110α, not p110β, resulted in increased adiposity, glucose intolerance and liver steatosis. Mice lacking p110α in adipose tissue exhibited a decrease in energy expenditure but no change in food intake or activity compared with control animals. This low energy expenditure is a consequence of low cellular respiration in the brown adipocytes caused by a decrease in expression of key mitochondrial genes including uncoupling protein-1. These results illustrate a critical role of p110α in the regulation of energy expenditure through modulation of cellular respiration in the brown adipose tissue and suggest that compromised insulin signaling in adipose tissue might be involved in the onset of obesity.

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