Bone morphogenetic protein 7 (BMP7) reverses obesity and regulates appetite through a central mTOR pathway

Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical School, Boston, MA 02215, USA.
The FASEB Journal (Impact Factor: 5.04). 02/2012; 26(5):2187-96. DOI: 10.1096/fj.11-199067
Source: PubMed


Body weight is regulated by coordinating energy intake and energy expenditure. Transforming growth factor β (TGFβ)/bone morphogenetic protein (BMP) signaling has been shown to regulate energy balance in lower organisms, but whether a similar pathway exists in mammals is unknown. We have previously demonstrated that BMP7 can regulate brown adipogenesis and energy expenditure. In the current study, we have uncovered a novel role for BMP7 in appetite regulation. Systemic treatment of diet-induced obese mice with BMP7 resulted in increased energy expenditure and decreased food intake, leading to a significant reduction in body weight and improvement of metabolic syndrome. Similar degrees of weight loss with reduced appetite were also observed in BMP7-treated ob/ob mice, suggesting a leptin-independent mechanism utilized by BMP7. Intracerebroventricular administration of BMP7 to mice led to an acute decrease in food intake, which was mediated, at least in part, by a central rapamycin-sensitive mTOR-p70S6 kinase pathway. Together, these results underscore the importance of BMP7 in regulating both food intake and energy expenditure, and suggest new therapeutic approaches for obesity and its comorbidities.

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    • "COMMON GENES SHARED BY OBESITY, CRC AND OSTEOPOROSIS, AND PLAUSIBLE EVIDENCE SUPPORTING THEIR RELATIONSHIPS WITH THE THREE DISEASES. GENES OBESITY CRC OSTEOPOROSIS PPP1R15A* In the bone morphogenetic protein (BMP) signaling pathway, which regulates appetite [34] Mutations in the BMP pathway are related with colorectal carcinogenesis [35] In the bone morphogenetic protein signaling pathway, which are associated with bone-related diseases, such as osteoporosis [36] FOS diet-induced obesity is accompanied by alteration of FOS expression [37] Proto-oncogene, in the KEGG pathway of colorectal cancer [38] Mice lacking c-fos develop severe osteopetrosis [39] FOSB positive association between maternal obesity [40] Oncogene, regulators of cell proliferation, has a debatable impact on CRC patient survival [41] Overexpression of FosB increases bone formation [42] HADHA* Associated with multiple fatty acid metabolism pathways [43] Unknown. Associated with breast cancer [44] Unknown. "
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    ABSTRACT: Epidemiological studies suggested that obesity increases the risk of colorectal cancer (CRC). The genetic connection between CRC and obesity is multifactorial and inconclusive. In this study, we hypothesize that the study of shared comorbid diseases between CRC and obesity can offer unique insights into common genetic basis of these two diseases. We constructed a comorbidity network based on mining health data for millions of patients. We developed a novel approach and extracted the diseases that play critical roles in connecting obesity and CRC in the comorbidity network. Our approach was able to prioritize metabolic syndrome and diabetes, which are known to be associated with obesity and CRC through insulin resistance pathways. Interestingly, we found that osteoporosis was highly associated with the connection between obesity and CRC. Through gene expression meta-analysis, we identified novel genes shared among CRC, obesity and osteoporosis. Literature evidences support that these genes may contribute in explaining the genetic overlaps between obesity and CRC.
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    • "Amino acids, glucose, and growth factors induce mTORC1 activation in the hypothalamus and reduce food intake. In addition to leucine and leptin, CNTF (Cota et al., 2008) and bone morphogenic protein 9 (BMP9; Townsend et al., 2012) also suppress food intake. Culture studies have revealed that these molecules elicit mTORC1 signaling in neuronal cells. "
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    ABSTRACT: Food intake is intricately regulated by glucose, amino acids, hormones, neuropeptides, and trophic factors through a neural circuit in the hypothalamus. Brain-derived neurotrophic factor (BDNF), the most prominent neurotrophic factor in the brain, regulates differentiation, maturation, and synaptic plasticity throughout life. Among its many roles, BDNF exerts an anorexigenic function in the brain. However, the intracellular signaling induced by BDNF to control food intake is not fully understood. One candidate for the molecule involved in transducing the anorexigenic activity of BDNF is the mammalian target of rapamycin (mTOR). mTOR senses extracellular amino acids, glucose, growth factors, and neurotransmitters, and regulates anabolic reactions response to these signals. Activated mTOR increases protein and lipid synthesis and inhibits protein degradation. In the hypothalamus, mTOR activation is thought to reduce food intake. Here we summarize recent findings regarding BDNF- and mTOR-mediated feeding control, and propose a link between these molecules in eating behavior.
    Frontiers in Psychology 09/2014; 5:1093. DOI:10.3389/fpsyg.2014.01093 · 2.80 Impact Factor
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    • "Various circulating peptides have been shown to be capable of activating BAT via the hypothalamus, such as GLP-1 [28] and BMP8B, another member of the BMP family [29]. In addition, Townsend et al. [25] showed that central administration of BMP7 resulted in reduced food intake, confirming that BMP7 is at least capable of exerting central effects. However, it remains to be determined whether subcutaneously administered BMP7 is able to enter the hypothalamus to subsequently exert central actions. "
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    ABSTRACT: Brown 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. High-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. Together, 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.
    PLoS ONE 09/2013; 8(9):e74083. DOI:10.1371/journal.pone.0074083 · 3.23 Impact Factor
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