The farnesoid X receptor (FXR) regulates bile acid, lipid and glucose metabolism. Here we show that treatment of mice with glycine-β-muricholic acid (Gly-MCA) inhibits FXR signalling exclusively in intestine, and improves metabolic parameters in mouse models of obesity. Gly-MCA is a selective high-affinity FXR inhibitor that can be administered orally and prevents, or reverses, high-fat diet-induced and genetic obesity, insulin resistance and hepatic steatosis in mice. The high-affinity FXR agonist GW4064 blocks Gly-MCA action in the gut, and intestine-specific Fxr-null mice are unresponsive to the beneficial effects of Gly-MCA. Mechanistically, the metabolic improvements with Gly-MCA depend on reduced biosynthesis of intestinal-derived ceramides, which directly compromise beige fat thermogenic function. Consequently, ceramide treatment reverses the action of Gly-MCA in high-fat diet-induced obese mice. We further show that FXR signalling in ileum biopsies of humans positively correlates with body mass index. These data suggest that Gly-MCA may be a candidate for the treatment of metabolic disorders.

Berardinelli-Seip congenital lipodystrophy type 2 (BSCL2) is the most severe form of human lipodystrophy, characterized by an almost complete loss of adipose tissue and severe insulin resistance. BSCL2 is caused by loss-of-function mutations in the BSCL2/SEIPIN gene, which is upregulated during adipogenesis and abundantly expressed in the adipose tissue. The physiological function of SEIPIN in mature adipocytes, however, remains to be elucidated. Here, we generated adipose-specific Seipin knockout (ASKO) mice, which exhibit adipocyte hypertrophy with enlarged lipid droplets, reduced lipolysis, adipose tissue inflammation, progressive loss of white and brown adipose tissue, insulin resistance, and hepatic steatosis. Lipidomic and microarray analyses revealed accumulation/imbalance of lipid species, including ceramides, in ASKO adipose tissue as well as increased endoplasmic reticulum stress. Interestingly, the ASKO mice almost completely phenocopy the fat-specific peroxisome proliferator–activated receptor-γ (Pparγ) knockout (FKO-γ) mice. Rosiglitazone treatment significantly improved a number of metabolic parameters of the ASKO mice, including insulin sensitivity. Our results therefore demonstrate a critical role of SEIPIN in maintaining lipid homeostasis and function of adipocytes and reveal an intimate relationship between SEIPIN and PPAR-γ.

The soluble complexes formed between hydrolyzed soybean protein and calcium at pH 7.4 were investigated using dialysis, gel chromatography, and Fourier transform infrared spectrometry (FTIR). The results demonstrate that the amount of calcium bound was significantly different for soybean protein hydrolysates obtained using the proteases neutrase, flavourzyme, protease M, and pepsin. Maximum levels of calcium binding (66.9 mg/g) occurred with hydrolysates produced using protease M. Peptide fragments exhibiting high calcium binding capacity had molecular weights of either 14.4 kDa or 8 to 9 kDa, and the calcium binding capacity was linearly correlated with carboxyl group content (R(2)= 0.8204). FTIR experiments revealed that upon binding calcium, the amide I band underwent a shift to lower wave numbers. A wide, intense Ca-O absorption band also appeared between 400 and 100 cm(-1) in the far-infrared spectrum. The width and intensity of this band increased after treatment of samples with glutaminase. The amount of bound calcium was related to both the molecular weight of the peptides and to the carboxyl group content, and the most likely sites for calcium binding are the carboxyl groups of Asp and Glu.

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Adrenomedullin 2 (ADM2) is an endogenous bioactive peptide belonging to the calcitonin gene-related peptide family. Our previous studies showed that overexpression of ADM2 in mice reduced obesity and insulin resistance by increasing thermogenesis in brown adipose tissue. However, the effects of ADM2 in another type of thermogenic adipocyte, beige adipocytes, remain to be understood. The plasma ADM2 levels were inversely correlated with obesity in humans, and adipo-ADM2-transgenic (tg) mice displayed resistance to high-fat diet-induced obesity with increased energy expenditure. Beiging of subcutaneous white adipose tissues (WAT) was more noticeably induced in high-fat diet-fed transgenic mice with adipocyte-ADM2 overexpression (adipo-ADM2-tg mice) than in WT animals. ADM2 treatment in primary rat subcutaneous adipocytes induced beiging with up-regulation of UCP1 and beiging-related marker genes and increased mitochondrial uncoupling respiration, which was mainly mediated by activation of the calcitonin receptor-like receptor (CRLR)⅐receptor activitymodifying protein 1 (RAMP1) complex and PKA and p38 MAPK signaling pathways. Importantly, this adipocyte-autonomous beiging effect by ADM2 was translatable to human primary adipocytes. In addition, M2 macrophage activation also contributed to the beiging effects of ADM2 through catecholamine secretion. Therefore, our study reveals that ADM2 enhances subcutaneous WAT beiging via a direct effect by activating the CRLR⅐RAMP1-cAMP/PKA and p38 MAPK pathways in white adipocytes and via an indirect effect by stimulating alternative M2 polarization in macrophages. Through both mechanisms, beiging of WAT by ADM2 results in increased energy expenditure and reduced obesity, suggesting ADM2 as a novel anti-obesity target.An imbalance between energy intake and energy expenditure is the cause for the development of obesity, which is a high risk factor for type 2 diabetes and related metabolic disorders. Adaptive thermogenesis in adipose tissue is an important contributor to overall energy expenditure; thus, enhancing thermogenesis in adipose tissue is considered one of the promising therapeutic strategies to improve energy homeostasis (1).In contrast to white adipose tissue (WAT), 3 which stores energy as triglycerides, brown adipose tissue (BAT) dissipates energy as heat by uncoupling protein 1 (UCP1)-mediated uncoupling of the mitochondrial respiratory chain from ATP synthesis (2). Upon stimuli such as ␤-3 adrenergic agonists or cold challenge, some adipocytes within WAT can exhibit brown-like features (3, 4) and have been identified as the third type of adipocytes, named "brite" (brown-in-white) or "beige" adipocytes (5). This biological process is referred to as WAT "browning" or "beiging" (3).Studies in both rodents and humans indicated that beiging of WAT increases the whole-body metabolic rate and improves energy homeostasis in obesity and type 2 diabetes (3, 6 -10). Enhancing WAT beiging alone was sufficient to alleviate obesity in mice (6), and emerging evidence also sugges...