Abstract
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.
Highlights
Human adipose tissue is broadly classified as either white adipose tissue (WAT) or brown adipose tissue (BAT)
High-fat diet fed lean C57Bl6/J mice were treated with Bone Morphogenetic Protein 7 (BMP7) via subcutaneous osmotic minipumps for 4 weeks at 21uC or 28uC, the latter being a thermoneutral temperature in which sympathetic activation of BAT is largely diminished
BMP7 diminished white adipose tissue (WAT) mass, accompanied by increased expression of genes related to intracellular lipolysis in WAT
Summary
Human adipose tissue is broadly classified as either white adipose tissue (WAT) or brown adipose tissue (BAT). WAT functions as an energy storage depot characterized by a large intracellular lipid droplet per adipocyte and is a prominent endocrine organ, producing hormones that regulate appetite and satiety [1]. BAT is an energy dissipation depot characterized by multi-locular lipid droplets per adipocyte and a wealth of densely packed mitochondria. Uncoupling protein-1 (UCP-1) in these mitochondria uncouples respiration from ATP synthesis, leading to heat production [2]. The most well-known trigger for activation of BAT is cold, which increases sympathetic outflow from the hypothalamic temperature centre towards BAT, leading to release of noradrenalin and increased thermogenesis. A second alternative pathway was demonstrated to control thermogenesis, in which alternatively activated (M2) macrophages release noradrenalin to activate BAT locally [3]
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