Final Report Summary - BMP 8B THERMOGENESIS (Role of Bone Morphogenic Protein 8b (BMP8b) in thermogenesis) Changes in temperature and in diet can activate mechanisms controlling adaptative thermogenesis , which regulation is mediated by adrenergic stimulation from the sympathetic nervous system especially to brown adipose tissue (BAT) and skeletal muscle. Previously we found that in brown adipose tissue, BMP8b is physiologically induced under conditions of increased adaptive thermogenesis such as HFD and cold exposure. Moreover, BMP8b upregulation following acute cold exposure in paralleled by an increase in UCP1 mRNA level. Conversely, BMP8b expression is decreased in conditions of reduced thermogenesis demands e.g. thermoneutrality.Furthermore, BMP 8b KO mice fed both a chow and a HFD gain more weight than their WT littermates what is associated with increased fat mass. Basal oxygen consumption of KO mice fed a chow diet was lower than in WT controls while the increase in response to HFD observed in WT mice was blunted in the BMP8b KO. This indicates that BMP8b is important for BAT adaptation to HFD. This metabolic data was correlated with histological morphometric analysis showing that the brown adipose tissue had larger fat droplets in the KO mice, indicative of impaired BAT function. This is in accordance with the reduced expression of thermogenic genes, physiologically induced by HFD such as UCP-1, deiodinase II, PPARg and PGC1a.This project focused on the investigation of the role of Bone morphogenic protein 8b in thermogenesis with the following specific objectives: 1) to establish whether overexpression of BMP8b prevents the development of diet induced and genetic forms of obesity and insulin resistance, 2) to establish the role of BMP8b in the differentiation and function of white and brown adipocytes, 3) to identify signalling pathway mechanisms mediated by BMP8b.The metabolic and molecular phenotyping of the transgenic mouse overexpressing Bmp8b in BAT and WAT (BTa) in addition to the previously accumulated evidence coming from the KO mice, allowed us to partially elucidate the role of Bmp8b in thermogenesis. Bmp 8b overexpression in scWAT of four weeks old mice lead to an increase of the expression of genes involved in the thermogenic machinery such as UCP-1 and Deiodinase II. A similar pattern was observed in BAT and scWAT of Bta fed a HFD when compared to controls. These data indicate that Bmp8b overexpression switch on the HFD challenge and cold feeling. Mice at four weeks are just weaned and their thermogenic demand is higher that in adult. Moreover, Bta mice on HFD show an improved insulin sensitivity when compared to controls.The increased expression levels of thermogenic drivers following Bmp8b overexpression in scWAT of young and HFD fed mice, indicate a more brown phenotype of these white adipocytes, suggesting that Bmp8b overexpression can confer a more brownish appearance to this WAT depot.The molecular analysis of the BAT of both Bmp8b KO and transgenic mice allowed us to go a step further in the understanding of the signalling mechanisms mediated by Bmp8b. BMP8b KO mice showed a decreased BAT sensitivity to noradrenaline. In these conditions, they have increased expression of adrenoreceptors and signalling kinases downstream of NA receptors, but they show a reduction in CREB and P38 MAPK phosphorylation. Conversely, BMP8b overexpression in BAT of transgenic mice increases the sensitivity of brown adipocytes to NA, as assayed by pCREB levels and P38 MAPK phosphorylation. All these data highlight a possible role of Bmp8b as a modulator of thermogenesis, more specifically controlling the cellular response to noradrenergic stimulation.BMP8b offers an exciting possibility in terms of therapeutic strategies to increase thermogenesis in humans, offering a mechanism by which we can improve insulin sensitivity and energy homeostasis and consequently combat human obesity acting specifically on the BAT.1. Lowell, B. B. and B. M. Spiegelman, Nature, 2000. 404(6778): p. 652-60.