SummaryThermogenesis 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.

Sirtuins are homologues of the yeast transcriptional repressor Sir2p and are conserved from bacteria to humans. We report that human SIRT4 is localized to the mitochondria. SIRT4 is a matrix protein and becomes cleaved at amino acid 28 after import into mitochondria. Mass spectrometry analysis of proteins that coimmunoprecipitate with SIRT4 identified insulindegrading enzyme and the ADP/ATP carrier proteins, ANT2 and ANT3. SIRT4 exhibits no histone deacetylase activity but functions as an efficient ADP-ribosyltransferase on histones and bovine serum albumin. SIRT4 is expressed in islets of Langerhans and colocalizes with insulin-expressing ␤ cells. Depletion of SIRT4 from insulin-producing INS-1E cells results in increased insulin secretion in response to glucose. These observations define a new role for mitochondrial SIRT4 in the regulation of insulin secretion.Histone deacetylases are enzymes that catalyze the removal of acetyl groups from the ⑀-amino group of lysine residues and are separated into three classes. Sirtuins, the class III histone deacetylases, are homologous to the yeast transcriptional repressor, Sir2p, and are NAD ϩ -dependent enzymes (1-3). Seven sirtuins have been identified in the human genome (4, 5). They share a conserved Sir2 catalytic core domain and exhibit variable amino-and carboxyl-terminal extensions that contribute to their unique subcellular localization and may also regulate their catalytic activity.The subcellular distribution, substrate specificity, and cellular functions of sirtuins are quite diverse (reviewed in Refs. 1-3). SIRT1 is found in the nucleus, where it functions as a transcriptional repressor via histone deacetylation. SIRT1 can also regulate transcription by modifying the acetylation levels of transcription factors, such as MyoD, FOXO, p53, and NF-B (6 -12). The SIRT2 protein is found in the cytoplasm, where it associates with microtubules and deacetylates lysine 40 of ␣-tubulin (13). The SIRT3 protein is localized in the mitochondrial matrix (14, 15), where it is proteolytically processed at its NH 2 terminus, yielding a mature protein that has protein deacetylase activity (14). These observations indicate that the targets of sirtuins are not restricted to histone proteins but extend to acetylated proteins in other subcellular compartments.Sirtuins also differ in their substrate specificities. For instance, SIRT1, -2, and -3 have robust activity on chemically acetylated histone H4 peptides, whereas SIRT5 has weak but detectable activity, and SIRT4, -6, and -7 have no detectable activity on the same substrate (13). Interestingly, a sirtuin from Archaeoglobus fulgidus, Sir2-Af1, which has close homology with SIRT5, also has weak activity on a histone peptide but significantly stronger activity on an acetylated bovine serum albumin substrate (16,17). Similarly, both SIRT1 and SIRT2 can deacetylate p53; however, only SIRT2 deacetylates lysine 40 of ␣-tubulin (13, 17).Recently, SIRT6 was demonstrated to be a nuclear ADP-ribosyltransferase (18), whereas a T. brucei SI...

Our understanding of adipose tissue biology has progressed rapidly since the turn of the century. White adipose tissue has emerged as a key determinant of healthy metabolism and metabolic dysfunction. This realization is paralleled only by the confirmation that adult humans have heat-dissipating brown adipose tissue, an important contributor to energy balance and a possible therapeutic target for the treatment of metabolic disease. We propose that the development of successful strategies to target brown and white adipose tissues will depend on investigations that elucidate their developmental origins and cell-type-specific functional regulators.