Adipose tissue is central to the regulation of energy balance. Two functionally different types of fat are present in mammals: white adipose tissue (WAT), the primary site of triglyceride storage, and brown adipose tissue (BAT), which is specialized in energy expenditure and can counteract obesity1. Factors that specify the developmental fate and function of white and brown adipose tissue remain poorly understood2,3. Here, we demonstrate that while some members of the family of bone morphogenetic proteins (BMP) support white adipocyte differentiation, BMP-7 singularly promotes differentiation of brown preadipocytes even in the absence of the normally required hormonal induction cocktail. BMP-7 activates a full program of brown adipogenesis including induction of early regulators of brown fat fate PRDM164 and PGC-1 (PPARγ coactivator-1) α5, increased expression of brown fat defining marker uncoupling protein-1 (UCP-1) and adipogenic transcription factors peroxisome proliferator-activated receptor (PPAR)γ and CCAAT/enhancer-binding proteins (C/EBPs), and mitochondrial biogenesis via a p38 MAP kinase and PGC-1 dependent pathway. Moreover, BMP-7 triggers commitment of mesenchymal progenitor cells to a brown adipocyte lineage, and implantation of these cells into nude mice results in development of adipose tissue containing mostly brown adipocytes. BMP-7 knockout embryos show a marked paucity of brown fat and near complete absence of UCP-1 protein. Adenoviral-mediated expression of BMP-7 in mice results in a significant increase in brown, but not white, fat mass and leads to an increase in energy expenditure and reduced weight gain. These data reveal an important role of BMP-7 in promoting brown adipocyte differentiation and thermogenesis in vivo and in vitro, and provide a potential novel therapeutic approach for the treatment of obesity.

Objective To investigate whether placebo effects can experimentally be separated into the response to three components-assessment and observation, a therapeutic ritual (placebo treatment), and a supportive patient-practitioner relationship-and then progressively combined to produce incremental clinical improvement in patients with irritable bowel syndrome. To assess the relative magnitude of these components.

BackgroundPlacebo treatment can significantly influence subjective symptoms. However, it is widely believed that response to placebo requires concealment or deception. We tested whether open-label placebo (non-deceptive and non-concealed administration) is superior to a no-treatment control with matched patient-provider interactions in the treatment of irritable bowel syndrome (IBS).MethodsTwo-group, randomized, controlled three week trial (August 2009-April 2010) conducted at a single academic center, involving 80 primarily female (70%) patients, mean age 47±18 with IBS diagnosed by Rome III criteria and with a score ≥150 on the IBS Symptom Severity Scale (IBS-SSS). Patients were randomized to either open-label placebo pills presented as “placebo pills made of an inert substance, like sugar pills, that have been shown in clinical studies to produce significant improvement in IBS symptoms through mind-body self-healing processes” or no-treatment controls with the same quality of interaction with providers. The primary outcome was IBS Global Improvement Scale (IBS-GIS). Secondary measures were IBS Symptom Severity Scale (IBS-SSS), IBS Adequate Relief (IBS-AR) and IBS Quality of Life (IBS-QoL).FindingsOpen-label placebo produced significantly higher mean (±SD) global improvement scores (IBS-GIS) at both 11-day midpoint (5.2±1.0 vs. 4.0±1.1, p<.001) and at 21-day endpoint (5.0±1.5 vs. 3.9±1.3, p = .002). Significant results were also observed at both time points for reduced symptom severity (IBS-SSS, p = .008 and p = .03) and adequate relief (IBS-AR, p = .02 and p = .03); and a trend favoring open-label placebo was observed for quality of life (IBS-QoL) at the 21-day endpoint (p = .08).ConclusionPlacebos administered without deception may be an effective treatment for IBS. Further research is warranted in IBS, and perhaps other conditions, to elucidate whether physicians can benefit patients using placebos consistent with informed consent.Trial RegistrationClinicalTrials.gov NCT01010191

IntroductionIn mammals obesity results when caloric intake exceeds energy use (1). Information on the pathways regulating both feeding and energy expenditure has expanded remarkably in the past several years, and a number of novel hypothalamic peptides that either stimulate or inhibit feeding have been described (1). Among these peptides, melanin-concentrating hormone (MCH) is known to play an important role in feeding behavior (2-4). In the brain, MCH expression is limited to the lateral hypothalamus (5) and responds to nutritional signals, including fasting and leptin deficiency (3). Thus, expression is increased with fasting and is also markedly increased in the Lep ob /Lep ob mouse, which lacks leptin (3). When administered intracerebroventricularly (ICV), MCH leads to a rapid increase in feeding in rats (3, 4). Importantly, MCH ablation in mice leads to a syndrome of leanness associated with hypophagia and a relative increase in oxygen consumption (6).The lean phenotype of MCH-ablated mice is of particular interest (6), in that genetic ablation of neuropeptide-Y (NPY), another appetite-stimulating neuropeptide (7, 8), does not affect body weight (9) unless combined with other obesity genes (10). Indeed, MCH is thus far the only known hypothalamic peptide whose ablation results in leanness. This is in contrast to the number of peptides whose mutation or ablation leads to obesity. These peptides include leptin and the melanocortin-4 receptors (11), proopiomelanocortin (POMC) (12), and the serotonin IIC receptor (13).As MCH is a significant regulator of body weight whose absence leads to decreased percentage of body adiposity, we examined the possibility that overexpression of MCH eutopically in the lateral hypothalamus might lead to a syndrome of obesity. To examine this question we generated a line of transgenic animals overexpressing MCH (MCH-OE) in the lateral hypothalamus. On the original FVB background, mice were not obese on a standard diet. However, they became obese when the gene was bred to homozygosity and the animals were fed a high-fat diet. MCH-OE animals were hyperphagic, hyperleptinemic, and had higher blood glucose levels. Animals were also significantly hyperinsulinemic and failed to respond to an insulin challenge. Several lines of investigation suggest that the hypothalamic neuropeptide melanin-concentrating hormone (MCH) regulates body weight in mammals. Obese mice lacking functional leptin overexpress the MCH message in the fed or fasted state. Acute intracerebroventricular injection of MCH increases energy intake in rats. Mice lacking the MCH gene are lean. To test the hypothesis that chronic overexpression of MCH in mice causes obesity, we produced transgenic mice that overexpress MCH (MCH-OE) in the lateral hypothalamus at approximately twofold higher levels than normal mice. On the FVB genetic background, homozygous transgenic animals fed a high-fat diet ate 10% more and were 12% heavier at 13 weeks of age than wild-type animals, and they had higher systemic leptin levels. Blood gluco...

Commensal and enteroinvasive microbes in the human gut release bacterial flagellin, a specific microbial ligand of Toll-like receptor 5 (TLR5). However, the pathophysiological role of bacterial flagellin in gastrointestinal inflammation has not been determined. Here we evaluated the role of bacterial flagellin using native human colonic mucosa and the mouse colitis model of dextran sulfate sodium (DSS). We demonstrate that, in intact human colonic mucosa, the flagellin͞TLR5 response occurs only after exposure to the basolateral, not the apical, surface, implying a basolaterally polarized TLR5 response in human colonic mucosa. In this context, flagellin exposure to injured colonic mucosa due to DSS administration in mice resulted in a TLR5-associated response evaluated by in vivo activation of mitogen-activated protein kinase͞extracellu-lar signal-related kinase 1͞2 (MEK1͞2) and elevated IL-6, TNF-␣, and keratinocyte-derived chemokine production, whereas intact colonic mucosa did not respond to flagellin. Moreover, flagellin exposure to injured mouse colon in vivo, but not to intact colon, also significantly aggravated colonic inflammation, increased mouse mortality, and enhanced histopathological damage in the colonic mucosa. However, the TLR2-specific agonist, peptidoglycan or lipoteichoic acid, did not cause an inflammatory response in intact or DSS-injured mouse colon. Furthermore, intracolonic flagellin administration in mice causes severe apoptosis in colonic epithelium disrupted by DSS administration. These data suggest that intracolonic flagellin via TLR5 engagement is able to elicit inflammatory responses in disrupted colon, whereas the normal colon is not responsive to bacterial flagellin. These results demonstrate that bacterial flagellin plays an important role in the development and progress of colitis.innate immunity ͉ colitis ͉ commensal bacteria

Intestinal fibrosis is a major complication of Crohn disease (CD), but the precise mechanism by which it occurs is incompletely understood. As a result, specific therapies to halt or even reverse fibrosis have not been explored. Here, we evaluated the contribution of epithelial to mesenchymal transition (

The insulin/IGF-1 (insulin-like growth factor 1) signalling pathway promotes adipocyte differentiation via complex signalling networks. Here, using microarray analysis of brown preadipocytes that are derived from wild-type and insulin receptor substrate (Irs) knockout animals that exhibit progressively impaired differentiation, we define 374 genes/expressed-sequence tags whose expression in preadipocytes correlates with the ultimate ability of the cells to differentiate. Many of these genes, including preadipocyte factor-1 (Pref-1) and multiple members of the Wnt signalling pathway, are related to early adipogenic events. Necdin is also markedly increased in Irs knockout cells that cannot differentiate, and knockdown of necdin restores brown adipogenesis with downregulation of Pref-1 and Wnt10a expression. Insulin receptor substrate proteins regulate a necdin-E2F4 interaction that represses peroxisome-proliferator-activated receptor gamma (PPARgamma) transcription via a cyclic AMP response element binding protein (CREB)-dependent pathway. Together these define a key signalling network that is involved in brown preadipocyte determination.

Both environmental and genetic factors play important roles in the development of the metabolic syndrome. To elucidate how these factors interact under normal conditions, C57Bl/6 (B6) and 129S6/SvEvTac (129) mice were placed on a low-fat or high-fat diet. Over 18 weeks, the 129 strain developed features of the metabolic syndrome, notably obesity, hyperinsulinemia, and glucose intolerance only on the high-fat diet; the B6 strain on the other hand developed these features on both diets. High-fat feeding of both strains led to decreased serum triglycerides, hepatic steatosis, and hypercholesterolemia; however, B6 mice developed worse steatosis and a larger increase in LDL cholesterol. Both B6 background and high-fat feeding increased sterol regulatory element-binding protein-1c (SREBP-1c), a key regulator of lipogenic gene transcription, and its downstream targets. Stearoyl-CoA desaturase 1 (SCD1), an enzyme that regulates monounsaturated fatty acid (MUFA) synthesis, was also increased at the mRNA and enzyme activity levels by both high-fat feeding and B6 background. Furthermore, lipid analysis revealed increased hepatic triglycerides and MUFAs in B6 and high-fat-fed mice. Thus, dietary fat and genetic background act through SREBP-1c and SCD1 to affect hepatic lipid metabolism contributing to the development of the metabolic syndrome. Diabetes 54: 1314 -1323, 2005