Fatty acid synthesis in the central nervous system is implicated in the control of food intake and energy expenditure. An intermediate in this pathway, malonyl-CoA, mediates these effects. Malonyl-CoA is an established inhibitor of carnitine palmitoyltransferase-1 (CPT1), an outer mitochondrial membrane enzyme that controls entry of fatty acids into mitochondria and, thereby, fatty acid oxidation. CPT1c, a brain-specific enzyme with high sequence similarity to CPT1a (liver) and CPT1b (muscle) was recently discovered. All three CPTs bind malonyl-CoA, and CPT1a and CPT1b catalyze acyl transfer from various fatty acyl-CoAs to carnitine, whereas CPT1c does not. These findings suggest that CPT1c has a unique function or activation mechanism. We produced a targeted mouse knockout (KO) of CPT1c to investigate its role in energy homeostasis. CPT1c KO mice have lower body weight and food intake, which is consistent with a role as an energy-sensing malonyl-CoA target. Paradoxically, CPT1c KO mice fed a high-fat diet are more susceptible to obesity, suggesting that CPT1c is protective against the effects of fat feeding. CPT1c KO mice also exhibit decreased rates of fatty acid oxidation, which may contribute to their increased susceptibility to diet-induced obesity. These findings indicate that CPT1c is necessary for the regulation of energy homeostasis.acetyl-CoA carboxylase ͉ fatty acid synthase ͉ food intake ͉ malonyl-CoA ͉ obesity B ody weight is maintained by regulating food intake and energy expenditure. This balance is monitored by the central nervous system (CNS) in response to cytokine and endocrine signals, including leptin, ghrelin, obestatin, insulin, cholecystokinin, and peptide YY secreted by peripheral tissues. Concomitantly, parallel pathways in the CNS regulate energy balance by monitoring the availability of neuronal energy-rich metabolic substrates. Integration of these signals occurs in the hypothalamus and, ultimately, in higher brain centers where feeding behavior and energy expenditure are adjusted. Two primary indicators of energy surplus, glucose and fatty acids, are also monitored by subsets of hypothalamic neurons that modulate feeding behavior and energy expenditure (1). Fatty acids (2) and de novo fatty acid synthesis from glucose (3) are known to mediate these effects. Indeed, food intake and body weight have been shown to be altered by manipulating the activities of the enzymes involved in fatty acid synthesis, e.g., fatty acid synthase (FAS) (3), malonyl-CoA decarboxylase (4, 5), acetyl-CoA carboxylase (ACC) (6, 7), stearoyl-CoA desaturase (8, 9), and 5Ј-AMP kinase (10, 11).Inhibition of FAS in the CNS, for example, reduces body weight by rapidly provoking a reduction in food intake and an increase in peripheral energy expenditure (3,12). This inhibition can reverse the weight gain caused by diet-induced obesity (13,14) or mutations in leptin (ob͞ob) or its receptor (db͞db) (3, 15), suggesting that it acts independently of STAT3, which is known to be essential for leptin 's action (16, 17). I...

Angiopoietin-related growth factor (AGF), a member of the angiopoietin-like protein (Angptl) family, is secreted predominantly from the liver into the systemic circulation. Here, we show that most (>80%) of the AGF-deficient mice die at about embryonic day 13, whereas the surviving AGF-deficient mice develop marked obesity, lipid accumulation in skeletal muscle and liver, and insulin resistance accompanied by reduced energy expenditure relative to controls. In parallel, mice with targeted activation of AGF show leanness and increased insulin sensitivity resulting from increased energy expenditure. They are also protected from high-fat diet-induced obesity, insulin resistance and nonadipose tissue steatosis. Hepatic overexpression of AGF by adenoviral transduction, which leads to an approximately 2.5-fold increase in serum AGF concentrations, results in a significant (P < 0.01) body weight loss and increases insulin sensitivity in mice fed a high-fat diet. This study establishes AGF as a new hepatocyte-derived circulating factor that counteracts obesity and related insulin resistance.

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We report here the identification of an angiopoietin-related growth factor (AGF). To examine the biological function of AGF in vivo, we created transgenic mice expressing AGF in epidermal keratinocytes (K14-AGF). K14-AGF mice exhibited swollen and reddish ears, nose and eyelids. Histological analyses of K14-AGF mice revealed significantly thickened epidermis and a marked increase in proliferating epidermal cells as well as vascular cells in the skin compared with nontransgenic controls. In addition, we found rapid wound closure in the healing process and an unusual closure of holes punched in the ears of K14-AGF mice. Furthermore, we observed that AGF is expressed in platelets and mast cells, and detected at wounded skin, whereas there was no expression of AGF detected in normal skin tissues, suggesting that AGF derived from these infiltrated cells affects epidermal proliferation and thereby plays a role in the wound healing process. These findings demonstrate that biological functions of AGF in epidermal keratinocytes could lead to novel therapeutic strategies for wound care and epidermal regenerative medicine. S kin tissues, especially epidermis, are a barrier against the environment, which becomes accessible in wounds and various infections. An important goal in wound management is to achieve rapid wound closure. Analysis of gene activation in skin tissues shows that transforming growth factor-␣ (TGF-␣) (1) produced by keratinocytes and keratinocyte growth factor (KGF) (2, 3) made by dermal fibroblasts are both powerful growth factors for epidermal keratinocytes, indicating an important role for the interaction between dermis-epidermis in skin development. Although these two growth factors play critical roles in wound healing, gene inactivation studies show that these factors are not essential for epidermal growth or regeneration and suggest that regulation of epidermal growth is more complex than has been previously appreciated (4, 5).Angiopoietin-1 (Ang-1) (6) is a ligand for the receptor tyrosine kinase TIE2 (7,8), which contributes to signaling in angiogenesis (9). Ang-1 is characterized structurally by two domains, a coiled-coil domain and a fibrinogen-like domain (10). Recently, members of the angiopoietins (Angs) family have been identified by a domain homology-based molecular cloning strategy. One of these proteins, angiopoietin-related protein 2 (ARP2), was also reported as an angiogenic factor (11). Several recent reports demonstrate that angiopoietin-related proteins (ARPs) show pleiotropic effects not only on vascular cells but on cells of other lineages. For example, it has been shown that ANGPTL3 (12, 13) and FIAF͞PGAR͞ARP4 (14) may play central roles in lipid͞adipocyte metabolism as well as in angiogenesis. Here we identify, by screening EST databases, a previously undescribed angiopoietin-related growth factor (AGF), which is abundantly expressed in hepatocytes. To determine whether AGF promotes in vivo angiogenesis as does Ang-1, we created transgenic (TG) mice overexpressing mouse AGF in epi...