scholarly journals Thermoneutrality induces skeletal muscle myopathy via brown adipose tissue in an IRF4- and myostatin-dependent manner

2018 ◽  
Author(s):  
Xingxing Kong ◽  
Peng Zhou ◽  
Ting Yao ◽  
Lawrence Kazak ◽  
Danielle Tenen ◽  
...  
Keyword(s):  
Gene Expression ◽  
Skeletal Muscle ◽  
Adipose Tissue ◽  
Brown Adipose Tissue ◽  
Exercise Capacity ◽  
Mitochondrial Function ◽  
Muscle Function ◽  
List Type ◽  
Wild Type ◽  
Brown Adipose

SummarySkeletal muscle and brown adipose tissue (BAT) share a common lineage and have been functionally linked, as exercise increases browning through the actions of various myokines. It is unknown, however, whether BAT can affect skeletal muscle function. Our prior work has shown that loss of the transcription factor IRF4 in BAT (BATI4KO) reduces adaptive thermogenesis. Here, we note that these mice also have reduced exercise capacity relative to wild-type littermates, associated with diminished mitochondrial function, ribosomal protein synthesis, and mTOR signaling in muscle, in addition to the signature ultrastructural abnormalities of tubular aggregate myopathy. Within brown adipose tissue, loss of IRF4 caused the induction of a myogenic gene expression signature, which includes an increase in the secreted factor myostatin, a known inhibitor of muscle function. Reduction of myostatin activity by the injection of neutralizing antibodies or soluble ActRIIB receptor rescued the exercise capacity of BATI4KO mice. Additionally, overexpression of IRF4 in brown adipocytes reduced serum myostatin and increased mitochondrial function and exercise capacity in muscle. A physiological role for this system is suggested by the observation that mice housed at thermoneutrality show lower exercise capacity with increased serum myostatin; both of these abnormalities are corrected by surgical removal of BAT. Collectively, our data point to an unsuspected level of BAT-muscle cross-talk driven by IRF4 and myostatin.HighlightsMice lacking IRF4 in BAT have a decrease in exercise capacity, accompanied by histological, ultrastructural, signaling, gene expression, and bioenergetic evidence of myopathy in white vastus.Loss of IRF4 promotes the expression of a myogenic signature in BAT, including the myokine myostatin.Neutralization of serum myostatin rescues the ability of BATI4KO mice to exercise normally, while overexpression of IRF4 in BAT allows mice to run better than wild-type counterparts.Thermoneutrality reduces the level of IRF4 in BAT of WT mice, resulting in a myopathic phenotype that can be reversed by surgical excision of BAT.

scholarly journals Chronic dietary supplementation of proanthocyanidins corrects the mitochondrial dysfunction of brown adipose tissue caused by diet-induced obesity in Wistar rats

2011 ◽  
Vol 107 (2) ◽  
pp. 170-178 ◽  
Author(s):  
David Pajuelo ◽  
Helena Quesada ◽  
Sabina Díaz ◽  
Anabel Fernández-Iglesias ◽  
Anna Arola-Arnal ◽  
...  
Keyword(s):  
Gene Expression ◽  
Adipose Tissue ◽  
Brown Adipose Tissue ◽  
Mitochondrial Dysfunction ◽  
Mitochondrial Function ◽  
Citrate Synthase ◽  
Sirtuin 1 ◽  
Male Rats ◽  
Diet Induced Obesity ◽  
Brown Adipose

The present study aims to determine the effects of grape seed proanthocyanidin extract (GSPE) on brown adipose tissue (BAT) mitochondrial function in a state of obesity induced by diet. Wistar male rats were fed with a cafeteria diet (Cd) for 4 months; during the last 21 d, two groups were treated with doses of 25 and 50 mg GSPE/kg body weight. In the BAT, enzymatic activities of citrate synthase, cytochrome c oxidase (COX) and ATPase were determined and gene expression was analysed by real-time PCR. The mitochondrial function of BAT was determined in fresh mitochondria by high-resolution respirometry using both pyruvate and carnitine–palmitoyl-CoA as substrates. The results show that the Cd causes an important decrease in the gene expression of sirtuin 1, nuclear respiratory factor 1, isocitrate dehydrogenase 3γ and COX5α and, what is more telling, decreases the levels of mitochondrial respiration both with pyruvate and canitine–palmitoyl-CoA. Most of these parameters, which are indicative of mitochondrial dysfunction due to diet-induced obesity, are improved by chronic supplementation of GSPE. The beneficial effects caused by the administration of GSPE are exhibited as a protection against weight gain, in spite of the Cd the rats were fed. These data indicate that chronic consumption of a moderate dose of GSPE can correct an energy imbalance in a situation of diet-induced obesity, thereby improving the mitochondrial function and thermogenic capacity of the BAT.

scholarly journals Brown Adipose Tissue Controls Skeletal Muscle Function via the Secretion of Myostatin

2018 ◽  
Vol 28 (4) ◽  
pp. 631-643.e3 ◽  
Author(s):  
Xingxing Kong ◽  
Ting Yao ◽  
Peng Zhou ◽  
Lawrence Kazak ◽  
Danielle Tenen ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Adipose Tissue ◽  
Brown Adipose Tissue ◽  
Muscle Function ◽  
Skeletal Muscle Function ◽  
Brown Adipose

scholarly journals Regulation of gene expression by FSP27 in white and brown adipose tissue

BMC Genomics ◽  
2010 ◽  
Vol 11 (1) ◽  
pp. 446 ◽  
Author(s):  
De Li ◽  
Yinxin Zhang ◽  
Li Xu ◽  
Linkang Zhou ◽  
Yue Wang ◽  
...  
Keyword(s):  
Gene Expression ◽  
Adipose Tissue ◽  
Brown Adipose Tissue ◽  
Regulation Of Gene Expression ◽  
Brown Adipose

scholarly journals Plasticity of non-shivering thermogenesis and brown adipose tissue in high-altitude deer mice

2021 ◽  
Author(s):  
Soren Z. Coulson ◽  
Cayleih E. Robertson ◽  
Sajeni Mahalingam ◽  
Grant B. McClelland
Keyword(s):  
Adipose Tissue ◽  
Brown Adipose Tissue ◽  
High Altitude ◽  
Heat Production ◽  
Mitochondrial Function ◽  
Mitochondrial Respiration ◽  
Deer Mice ◽  
Brown Adipose ◽  
Hypoxia Acclimation ◽  
Shivering Thermogenesis

High altitude environments challenge small mammals with persistent low ambient temperatures that require high rates of aerobic heat production in face of low O2 availability. An important component of thermogenic capacity in rodents is non-shivering thermogenesis (NST) mediated by uncoupled mitochondrial respiration in brown adipose tissue (BAT). NST is plastic, and capacity for heat production increases with cold acclimation. However, in lowland native rodents, hypoxia inhibits NST in BAT. We hypothesize that highland deer mice (Peromyscus maniculatus) overcome the hypoxic inhibition of NST through changes in BAT mitochondrial function. We tested this hypothesis using lab born and raised highland and lowland deer mice, and a lowland congeneric (P. leucopus), acclimated to either warm normoxia (25°C, 760 mmHg) or cold hypoxia (5°C, 430 mmHg). We determined the effects of acclimation and ancestry on whole-animal rates of NST, the mass of interscapular BAT (iBAT), and uncoupling protein (UCP)-1 protein expression. To identify changes in mitochondrial function, we conducted high-resolution respirometry on isolated iBAT mitochondria using substrates and inhibitors targeted to UCP-1. We found that rates of NST increased with cold hypoxia acclimation but only in highland deer mice. There was no effect of cold hypoxia acclimation on iBAT mass in any group, but highland deer mice showed increases in UCP-1 expression and UCP-1 stimulated mitochondrial respiration in response to these stressors. Our results suggest that highland deer mice have evolved to increase the capacity for NST in response to chronic cold hypoxia, driven in part by changes in iBAT mitochondrial function.

Abstract 12631: Peripheral Gamma-aminobutyric Acid(gaba) Signaling in Brown Adipose Tissue Induces Metabolic Dysfunction in Obesity

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Ryutaro Ikegami ◽  
Ippei Shimizu ◽  
Takeshi Sato ◽  
Shuang Jiao ◽  
Yohko Yoshida ◽  
...  
Keyword(s):  
Nervous System ◽  
Adipose Tissue ◽  
Brown Adipose Tissue ◽  
Mitochondrial Function ◽  
Aminobutyric Acid ◽  
Mitochondrial Calcium ◽  
Metabolic Dysfunction ◽  
Gamma Aminobutyric Acid ◽  
Brown Adipose ◽  
Gaba Signaling

Accumulating evidence suggests that adult humans possess active brown adipose tissue (BAT) that may contribute significantly to systemic metabolism because of its high energy consumption capacity. Recently, we demonstrated that metabolic stress induced BAT hypoxia and impaired mitochondrial function, leading to the development of BAT “whitening” and systemic metabolic dysfunction in murine obese models. Various neurotransmitters are known to be involved in the maintenance of BAT homeostasis. Among them, the gamma-aminobutyric acid (GABA) signaling in the central nervous system is well accepted to have anti-obesity effects through the activation of the sympathetic nervous system. Here we show the previously unknown role of peripheral GABA signaling in the development of systemic metabolic dysfunction in obesity. We generated an obese model by imposing a high fat/high sucrose (HFHS) diet on C57BL/6NCr mice. Mass spectrometry analysis demonstrated a significant increase in GABA level in BAT of the dietary obese model. Addition of GABA into drinking water induced BAT whitening, reduced the thermogenic response upon cold tolerance test, and promoted systemic metabolic dysfunction in the obese mice. Mitochondrial calcium is important for the maintenance of mitochondrial homeostasis, whereas calcium overload is reported to inhibit mitochondrial function. Treatment of BAT cells with GABA markedly increased mitochondrial calcium level, promoted the production of reactive oxygen species (ROS), and inhibited mitochondrial respiration. These results indicate that peripheral GABA contributes to the development of systemic metabolic dysfunction by inhibiting BAT function in obesity. The inhibition of peripheral GABA signaling would become a new therapeutic target for obesity and diabetes.

Effect of hypothyroidism on adenylyl cyclase activity and subtype gene expression in brown adipose tissue

1997 ◽  
Vol 273 (2) ◽  
pp. R762-R767 ◽  
Author(s):  
A. Chaudhry ◽  
J. G. Granneman
Keyword(s):  
Gene Expression ◽  
Adipose Tissue ◽  
Brown Adipose Tissue ◽  
Adenylyl Cyclase ◽  
Regulation Of Gene Expression ◽  
Mrna Levels ◽  
Adrenergic Stimulation ◽  
Functional Responses ◽  
Synergistic Interactions ◽  
Brown Adipose

Brown adipose tissue (BAT) expresses several adenylyl cyclase (AC) subtypes, and adrenergic stimulation selectively upregulates AC-III gene expression. Previous studies have described synergistic interactions between the sympathetic nervous system (SNS) and 3,5,3'-triiodothyronine (T3) on the regulation of gene expression in BAT. Because adrenergic stimulation also increases the activity of BAT type II thyroxine 5'-deiodinase (DII) and local T3 generation is important for many functional responses in BAT, we examined the effects of thyroid hormone status on the expression of various AC subtypes. Hypothyroidism selectively increased AC-III mRNA levels in BAT but not in white adipose tissue. Of the other subtypes examined, hypothyroidism did not alter AC-VI mRNA levels and slightly reduced AC-IX mRNA levels in BAT. The increase in AC-III expression was paralleled by an increase in forskolin-stimulated AC activity in BAT membranes. Sympathetic denervation of BAT abolished the increase in both AC activity and AC-III mRNA expression produced by hypothyroidism, but did not affect the expression of other subtypes. Surgical denervation also prevented the induction of AC-III in the cold-stressed euthyroid rat, but injections of T3 failed to alter AC-III expression in intact or denervated BAT. Our results indicate that T3 does not directly affect expression of AC-III. Rather, hypothyroidism increases BAT AC-III expression indirectly via an increase in sympathetic stimulation. Furthermore, our results strongly indicate that the increase in AC activity in hypothyroid BAT is due to increased expression of AC-III.

Inhibition by Oxytetracycline of the Development of the Enhanced Response to Noradrenaline in Cold-Acclimated Rats: A New Approach to the Study of Nonshivering Thermogenesis

1971 ◽  
Vol 49 (6) ◽  
pp. 545-553 ◽  
Author(s):  
Jean Himms–Hagen
Keyword(s):  
Skeletal Muscle ◽  
Adipose Tissue ◽  
Brown Adipose Tissue ◽  
Cytochrome Oxidase ◽  
Oxidase Activity ◽  
Metabolic Response ◽  
Inner Membrane ◽  
Cytochrome Oxidase Activity ◽  
Mitochondrial Inner Membrane ◽  
Brown Adipose

The aim of these experiments was to depress the increased metabolic activity of the brown adipose tissue in the intact rat during acclimation to cold in order to elucidate further the possible thermogenic and endocrine functions of this tissue. The antibiotic oxytetracycline was administered twice daily for 2 weeks to rats living at 4 °C in an attempt to inhibit the proliferation of mitochondria and of mitochondrial inner membrane known to occur in the brown adipose tissue in response to cold; control rats received saline during the same period. Total cytochrome oxidase activity served as an index of the amount of mitochondrial inner membrane in brown adipose tissue, liver, and skeletal muscle. The development of an enhanced calorigenic response to intravenously infused noradrenaline served as an index of the extent of acclimation to cold.Treatment with oxytetracycline inhibited both the cold-induced increase in cytochrome oxidase activity in brown adipose tissue and the cold-induced development of an enhanced calorigenic response to noradrenaline in the intact rats; a direct correlation was noted between the amount of cytochrome oxidase in brown adipose tissue and the size of the metabolic response to noradrenaline of the intact animals. However, the amount of oxygen that could be consumed by the total cytochrome oxidase in the brown adipose tissue was itself too small to account for the increase in oxygen consumption by the rat. Treatment of the rats with oxytetracycline did not alter the cold-induced growth of brown adipose tissue (as judged by the increase in wet weight and the increase in total protein); it also did not alter the cytochrome oxidase activities of liver or skeletal muscle. The effect of oxytetracycline seems, therefore, to be fairly specific for the mitochondria of the most rapidly dividing tissue, the brown adipose tissue. The conclusion is drawn that a protein synthesized in the mitochondria of the brown adipose tissue in response to cold is essential for adaptation to cold.

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