The glucocorticoid receptor in brown adipocytes is dispensable for control of energy homeostasis

Glantschnig, Christina; Mattijssen, Frits; Vogl, Elena Sophie; Khan, Asrar Ali; García, Marcos Ríos; Fischer, Katrin; Müller, Timo; Uhlenhaut, N. Henriette; Nawroth, Peter; Scheideler, Marcel; Rose, Adam J.; Pellegata, Natalia S.; Herzig, Stephan

doi:10.15252/embr.201948552

Cited by 17 publications

(17 citation statements)

References 39 publications

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“…In line with this, GR activity in adipose tissue was also not essential for maintaining BAT activity rhythm in vivo , as mice that lack adipocyte GR expression still exhibit the robust rhythm in BAT metabolic activity as observed in WT mice. In accordance, a recent study showed that the GR in brown adipocytes is not required for BAT-dependent energy homeostasis [ 29 ]. Corticosterone flattening also perturbed BAT activity rhythm in ad.GRKO mice, indicating that this effect is also independent on direct binding of corticosterone to the GR on brown adipocytes.…”

Section: Discussionsupporting

confidence: 78%

A physiological glucocorticoid rhythm is an important regulator of brown adipose tissue function

Kroon

Schilperoort

Panhuis

et al. 2021

Molecular Metabolism

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Objective Brown adipose tissue (BAT) displays a strong circadian rhythm in metabolic activity, but it is unclear how this rhythm is regulated. As circulating levels of corticosterone coincide with the rhythm of triglyceride-derived fatty acid (FA) uptake by BAT, we investigated whether corticosterone regulates BAT circadian rhythm. Methods Corticosterone levels were flattened by implanting mice with subcutaneous corticosterone-releasing pellets, resulting in constant circulating corticosterone levels. Results Flattened corticosterone rhythm caused a complete loss of circadian rhythm in triglyceride-derived fatty acid uptake by BAT. This effect was independent of glucocorticoid receptor expression in (brown) adipocytes and was not caused by deregulation of clock gene expression or overexposure to glucocorticoids, but rather seemed mediated by reduced sympathetic innervation of BAT. In a mouse model of hyperlipidemia and metabolic syndrome, long-term experimental flattening of corticosterone and thus rhythm in BAT function resulted in adiposity. Conclusions This study highlights that a physiological rhythm in glucocorticoids is an important regulator of BAT function and essential for the maintenance of metabolic health.

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Section: Discussionsupporting

confidence: 78%

A physiological glucocorticoid rhythm is an important regulator of brown adipose tissue function

Kroon

Schilperoort

Panhuis

et al. 2021

Molecular Metabolism

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“…Chronic GC treatment decreases UCP-1 activity in the BAT in rodents and in Human, whereas an acute treatment increases brown fat activity in humans, but not in rodents [ 103 ]. Recently, BAT-specific GR -KO mice show no change in insulin resistance in response to diet-induced obesity, nor are losing the capacity to thermoregulate [ 104 ]. Additionally, IR KO in brown adipocytes results in an insulin secretion defect and a glucose intolerance but without insulin resistance, indicating a different metabolic impact of the insulin resistance in the BAT vs. WAT [ 67 ].…”

Section: Long-term Glucocorticoid Exposure and Insulin Resistance mentioning

confidence: 99%

Molecular Mechanisms of Glucocorticoid-Induced Insulin Resistance

Beaupère

Liboz

Fève

et al. 2021

IJMS

105

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Glucocorticoids (GCs) are steroids secreted by the adrenal cortex under the hypothalamic-pituitary-adrenal axis control, one of the major neuro-endocrine systems of the organism. These hormones are involved in tissue repair, immune stability, and metabolic processes, such as the regulation of carbohydrate, lipid, and protein metabolism. Globally, GCs are presented as ‘flight and fight’ hormones and, in that purpose, they are catabolic hormones required to mobilize storage to provide energy for the organism. If acute GC secretion allows fast metabolic adaptations to respond to danger, stress, or metabolic imbalance, long-term GC exposure arising from treatment or Cushing’s syndrome, progressively leads to insulin resistance and, in fine, cardiometabolic disorders. In this review, we briefly summarize the pharmacological actions of GC and metabolic dysregulations observed in patients exposed to an excess of GCs. Next, we describe in detail the molecular mechanisms underlying GC-induced insulin resistance in adipose tissue, liver, muscle, and to a lesser extent in gut, bone, and brain, mainly identified by numerous studies performed in animal models. Finally, we present the paradoxical effects of GCs on beta cell mass and insulin secretion by the pancreas with a specific focus on the direct and indirect (through insulin-sensitive organs) effects of GCs. Overall, a better knowledge of the specific action of GCs on several organs and their molecular targets may help foster the understanding of GCs’ side effects and design new drugs that possess therapeutic benefits without metabolic adverse effects.

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“…Interestingly, in UCP1-deficient mice, GC-induced obesity was not worsened compared to wild-type mice (158), suggesting UCP1-independent effects of GCs on BAT function. Furthermore, based on a study analyzing BAT-specific GR knockout (GR BATKO ) male mice, the role of GR in BAT function is debatable, as GR BATKO mice did not differ from wild-type mice in terms of BAT thermogenesis and HFD-induced metabolic consequences (159). It should be noted that in the GR BATKO male mice the HPA axis was not affected and that these mice had normal corticosterone levels.…”

Section: Effects Of Glucocorticoids On Batmentioning

confidence: 99%

Sex Differences in Brown Adipose Tissue Function: Sex Hormones, Glucocorticoids, and Their Crosstalk

2021

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Excessive fat accumulation in the body causes overweight and obesity. To date, research has confirmed that there are two types of adipose tissue with opposing functions: lipid-storing white adipose tissue (WAT) and lipid-burning brown adipose tissue (BAT). After the rediscovery of the presence of metabolically active BAT in adults, BAT has received increasing attention especially since activation of BAT is considered a promising way to combat obesity and associated comorbidities. It has become clear that energy homeostasis differs between the sexes, which has a significant impact on the development of pathological conditions such as type 2 diabetes. Sex differences in BAT activity may contribute to this and, therefore, it is important to address the underlying mechanisms that contribute to sex differences in BAT activity. In this review, we discuss the role of sex hormones in the regulation of BAT activity under physiological and some pathological conditions. Given the increasing number of studies suggesting a crosstalk between sex hormones and the hypothalamic-pituitary-adrenal axis in metabolism, we also discuss this crosstalk in relation to sex differences in BAT activity.

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The glucocorticoid receptor in brown adipocytes is dispensable for control of energy homeostasis

Cited by 17 publications

References 39 publications

A physiological glucocorticoid rhythm is an important regulator of brown adipose tissue function

A physiological glucocorticoid rhythm is an important regulator of brown adipose tissue function

Molecular Mechanisms of Glucocorticoid-Induced Insulin Resistance

Sex Differences in Brown Adipose Tissue Function: Sex Hormones, Glucocorticoids, and Their Crosstalk

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