BMP8B Increases Brown Adipose Tissue Thermogenesis through Both Central and Peripheral ActionsThermogenesis in brown adipose tissue (BAT) is fundamental to energy balance and is also relevant for humans. Bone morphogenetic proteins (BMPs) regulate adipogenesis, and, here, we describe a role for BMP8B in the direct regulation of thermogenesis. BMP8B is induced by nutritional and thermogenic factors in mature BAT, increasing the response to noradrenaline through enhanced p38MAPK/CREB signaling and increased lipase activity. Bmp8b(-/-) mice exhibit impaired thermogenesis and reduced metabolic rate, causing weight gain despite hypophagia. BMP8B is also expressed in the hypothalamus, and Bmp8b(-/-) mice display altered neuropeptide levels and reduced phosphorylation of AMP-activated protein kinase (AMPK), indicating an anorexigenic state. Central BMP8B treatment increased sympathetic activation of BAT, dependent on the status of AMPK in key hypothalamic nuclei. Our results indicate that BMP8B is a thermogenic protein that regulates energy balance in partnership with hypothalamic AMPK. BMP8B may offer a mechanism to specifically increase energy dissipation by BAT.
Estradiol Regulates Brown Adipose Tissue Thermogenesis via Hypothalamic AMPKA Functional Link between AMPK and Orexin Mediates the Effect of BMP8B on Energy BalanceAMP-activated protein kinase (AMPK) in the ventromedial nucleus of the hypothalamus (VMH) and orexin (OX) in the lateral hypothalamic area (LHA) modulate brown adipose tissue (BAT) thermogenesis. However, whether these two molecular mechanisms act jointly or independently is unclear. Here, we show that the thermogenic effect of bone morphogenetic protein 8B (BMP8B) is mediated by the inhibition of AMPK in the VMH and the subsequent increase in OX signaling via the OX receptor 1 (OX1R). Accordingly, the thermogenic effect of BMP8B is totally absent in ox-null mice. BMP8B also induces browning of white adipose tissue (WAT), its thermogenic effect is sexually dimorphic (only observed in females), and its impact on OX expression and thermogenesis is abolished by the knockdown of glutamate vesicular transporter 2 (VGLUT2), implicating glutamatergic signaling. Overall, our data uncover a central network controlling energy homeostasis that may be of considerable relevance for obesity and metabolic disorders.
Hypothalamic mTOR Signaling Mediates the Orexigenic Action of GhrelinCurrent evidence suggests that ghrelin, a stomach derived peptide, exerts its orexigenic action through specific modulation of Sirtuin1 (SIRT1)/p53 and AMP-activated protein kinase (AMPK) pathways, which ultimately increase the expression of agouti-related protein (AgRP) and neuropeptide Y (NPY) in the arcuate nucleus of the hypothalamus (ARC). However, there is a paucity of data about the possible action of ghrelin on alternative metabolic pathways at this level. Here, we demonstrate that ghrelin elicits a marked upregulation of the hypothalamic mammalian target of rapamycin (mTOR) signaling pathway. Of note, central inhibition of mTOR signaling with rapamycin decreased ghrelin's orexigenic action and normalized the mRNA expression of AgRP and NPY, as well as their key downstream transcription factors, namely cAMP response-element binding protein (pCREB) and forkhead box O1 (FoxO1, total and phosphorylated). Taken together, these data indicate that, in addition to previous reported mechanisms, ghrelin also promotes feeding through modulation of hypothalamic mTOR pathway.
AMPK activation protects against diet-induced obesity through Ucp1-independent thermogenesis in subcutaneous white adipose tissue