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Diet-induced obesity causes insulin resistance in mouse brown adipose tissue.

ABSTRACT: OBJECTIVE:Diet-induced obesity (DIO) causes several pathophysiological changes in adipose tissue. Increased inflammation reduces white adipose tissue (WAT) insulin sensitivity and contributes to the development of diabetes. However, little is known about how DIO alters the function of brown adipose tissue (BAT), an organ that consumes calories by ?3-adrenergic receptor (AR)-mediated thermogenesis and helps regulate energy balance. METHODS:To test the effects of DIO on BAT, we fed 6-week-old C57BL/6 mice either a normal chow diet (NCD) or a high-fat diet (HFD). After 16 additional weeks, we measured body fat, WAT, and BAT mRNA expression, glucose tolerance, and rates of glucose uptake in response to insulin and the ?3-AR agonist mirabegron. RESULTS:Compared with NCD, HFD increased body fat and impaired glucose tolerance. Both WAT and BAT had higher mRNA levels of markers of inflammation, including TNF? and F4/80. Insulin signaling in BAT and WAT was reduced, with decreased Akt phosphorylation. Diet-normalized BAT glucose uptake rates were lower in response to mirabegron. CONCLUSIONS:These results support a model in which DIO leads to BAT inflammation and insulin resistance, leading to a broader impairment of BAT function.

SUBMITTER: Roberts-Toler C

PROVIDER: S-EPMC4551605 | biostudies-literature | 2015 Sep

REPOSITORIES: biostudies-literature

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Diet-induced obesity causes insulin resistance in mouse brown adipose tissue.

Roberts-Toler Carla C O'Neill Brian T BT Cypess Aaron M AM

Obesity (Silver Spring, Md.) 20150803 9

<h4>Objective</h4>Diet-induced obesity (DIO) causes several pathophysiological changes in adipose tissue. Increased inflammation reduces white adipose tissue (WAT) insulin sensitivity and contributes to the development of diabetes. However, little is known about how DIO alters the function of brown adipose tissue (BAT), an organ that consumes calories by β3-adrenergic receptor (AR)-mediated thermogenesis and helps regulate energy balance.<h4>Methods</h4>To test the effects of DIO on BAT, we fed ...[more]

PMID: 26242777

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Project description:Background/aimsBrown adipose tissue (BAT) dissipates energy stored in triglycerides as heat via the uncoupling protein UCP-1 and is a promising target to combat hyperlipidemia and obesity. BAT is densely innervated by the sympathetic nervous system, which increases BAT differentiation and activity upon cold exposure. Recently, Bone Morphogenetic Protein 7 (BMP7) was identified as an inducer of BAT differentiation. We aimed to elucidate the role of sympathetic activation in the effect of BMP7 on BAT by treating mice with BMP7 at varying ambient temperature, and assessed the therapeutic potential of BMP7 in combating obesity.Methods and resultsHigh-fat diet fed lean C57Bl6/J mice were treated with BMP7 via subcutaneous osmotic minipumps for 4 weeks at 21 °C or 28 °C, the latter being a thermoneutral temperature in which sympathetic activation of BAT is largely diminished. At 21 °C, BMP7 increased BAT weight, increased the expression of Ucp1, Cd36 and hormone-sensitive lipase in BAT, and increased total energy expenditure. BMP7 treatment markedly increased food intake without affecting physical activity. Despite that, BMP7 diminished white adipose tissue (WAT) mass, accompanied by increased expression of genes related to intracellular lipolysis in WAT. All these effects were blunted at 28 °C. Additionally, BMP7 resulted in extensive 'browning' of WAT, as evidenced by increased expression of BAT markers and the appearance of whole clusters of brown adipocytes via immunohistochemistry, independent of environmental temperature. Treatment of diet-induced obese C57Bl6/J mice with BMP7 led to an improved metabolic phenotype, consisting of a decreased fat mass and liver lipids as well as attenuated dyslipidemia and hyperglycemia.ConclusionTogether, these data show that BMP7-mediated recruitment and activation of BAT only occurs at subthermoneutral temperature, and is thus likely dependent on sympathetic activation of BAT, and that BMP7 may be a promising tool to combat obesity and associated disorders.

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Diet-induced obesity causes insulin resistance in mouse brown adipose tissue.

Publications

Diet-induced obesity causes insulin resistance in mouse brown adipose tissue.

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