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Background: Studies have suggested that the fat mass and obesityassociated (FTO) genotype is associated with individual variability in weight loss in response to diet/lifestyle interventions, but results are inconsistent. Objective: We aimed to provide a summary of the literature evaluating the relation between the FTO genotype and weight loss in response to diet/lifestyle interventions. Design: A search of English-language articles in the PubMed and Embase databases (through 30 April 2015) was performed. Eligible studies were diet/lifestyle weight-loss intervention studies conducted in adults that reported changes in body weight or body mass index (BMI) by the FTO variant rs9939609 (or its proxy). Differences in weight loss between FTO genotypes across studies were pooled with the use of fixed-effect models. Results: A meta-analysis of 10 studies (comprising 6951 participants) that reported the results of additive genetic models showed that individuals with the FTO TA genotype and AA genotype (those with the obesity-predisposing A allele) had 0.18-kg (95% CI: 20.09-, 0.45-kg; P = 0.19; NS) and 0.44-kg (95% CI: 0.09-, 0.79-kg; P = 0.015) greater weight loss, respectively, than those with the TT genotype. A metaanalysis of 14 studies (comprising 7700 participants) that reported the results of dominant genetic models indicated a 0.20-kg (20.43-, 0.04-kg) greater weight loss in the TA/AA genotype than in the TT genotype (P = 0.10). In addition, differences in weight loss between the AA genotype and TT genotype were significant in studies with a diet intervention only, adjustment for baseline BMI or body weight, and several other subgroups. However, the relatively small number of studies limited these stratified analyses, and there was no statistically significant difference between subgroups. Conclusions: This meta-analysis suggests that individuals carrying the homozygous FTO obesity-predisposing allele may lose more weight through diet/lifestyle interventions than noncarriers. Our data provide evidence for genetic variability in response to diet/lifestyle interventions on weight loss, although clinical applications of these findings need further investigations.

Whether bone marrow modulates systemic metabolism remains unknown. Here, we found that (i) myeloid cell–specific myeloid-derived growth factor (MYDGF) deficiency exacerbated vascular inflammation, adhesion responses, endothelial injury, and atherosclerosis in vivo. (ii) Myeloid cell–specific MYDGF restoration attenuated vascular inflammation, adhesion responses and leukocyte homing and alleviated endothelial injury and atherosclerosis in vivo. (iii) MYDGF attenuated endothelial inflammation, apoptosis, permeability, and adhesion responses induced by palmitic acid in vitro. (iv) MYDGF alleviated endothelial injury and atherosclerosis through mitogen-activated protein kinase kinase kinase kinase 4 (MAP4K4)/nuclear factor κB (NF-κB) signaling. Therefore, we concluded that MYDGF inhibits endothelial inflammation and adhesion responses, blunts leukocyte homing, protects against endothelial injury and atherosclerosis in a manner involving MAP4K4/NF-κB signaling, and serves as a cross-talk factor between bone marrow and arteries to regulate the pathophysiology of arteries. Bone marrow functions as an endocrine organ and serves as a potential therapeutic target for metabolic disorders.

Growth differentiation factor 11 (GDF11) has been implicated in the regulation of islet development and a variety of aging conditions, but little is known about the physiological functions of GDF11 in adult pancreatic islets. Here, we showed that systematic replenishment of GDF11 not only preserved insulin secretion but also improved the survival and morphology of β-cells and improved glucose metabolism in both nongenetic and genetic mouse models of type 2 diabetes (T2D). Conversely, anti-GDF11 monoclonal antibody treatment caused β-cell failure and lethal T2D. In vitro treatment of isolated murine islets and MIN6 cells with recombinant GDF11 attenuated glucotoxicity-induced β-cell dysfunction and apoptosis. Mechanistically, the GDF11-mediated protective effects could be attributed to the activation of transforming growth factor-β/Smad2 and phosphatidylinositol-4,5-bisphosphate 3-kinase-AKT-FoxO1 signaling. These findings suggest that GDF11 repletion may improve β-cell function and mass and thus may lead to a new therapeutic approach for T2D.

Aims/hypothesis Myeloid-derived growth factor (MYDGF), mainly secreted by bone marrow-derived cells, has been known to promote glucagon-like peptide-1 production and improve glucose/lipid metabolism in mouse models of diabetes, but little is known about the functions of MYDGF in diabetic kidney disease (DKD). Here, we investigated whether MYDGF can prevent the progression of DKD. Methods In vivo experiments, both loss-and gain-of-function strategies were used to evaluate the effect of MYDGF on albuminuria and pathological glomerular lesions. We used streptozotocin-treated Mydgf knockout and wild-type mice on high fat diets to induce a model of DKD. Then, albuminuria, glomerular lesions and podocyte injury were evaluated in Mydgf knockout and wild-type DKD mice treated with adeno-associated virus-mediated Mydgf gene transfer. In vitro and ex vivo experiments, the expression of slit diaphragm protein nephrin and podocyte apoptosis were evaluated in conditionally immortalised mouse podocytes and isolated glomeruli from non-diabetic wild-type mice treated with recombinant MYDGF. Results MYDGF deficiency caused more severe podocyte injury in DKD mice, including the disruption of slit diaphragm proteins (nephrin and podocin) and an increase in desmin expression and podocyte apoptosis, and subsequently caused more severe glomerular injury and increased albuminuria by 39.6% compared with those of wild-type DKD mice (p < 0.01). Inversely, MYDGF replenishment attenuated podocyte and glomerular injury in both wild-type and Mydgf knockout DKD mice and then decreased albuminuria by 36.7% in wild-type DKD mice (p < 0.01) and 34.9% in Mydgf knockout DKD mice (p < 0.01). Moreover, recombinant MYDGF preserved nephrin expression and inhibited podocyte apoptosis in vitro and ex vivo. Mechanistically, the renoprotection of MYDGF was attributed to the activation of the Akt/Bcl-2-associated death promoter (BAD) pathway. Conclusions/interpretationThe study demonstrates that MYDGF protects podocytes from injury and prevents the progression of DKD, providing a novel strategy for the treatment of DKD.