Common variants in WNT pathway genes have been associated with bone mass and fat distribution, the latter predicting diabetes and cardiovascular disease risk. Rare mutations in the WNT co-receptors LRP5 and LRP6 are similarly associated with bone and cardiometabolic disorders. We investigated the role of LRP5 in human adipose tissue. Subjects with gain-of-function LRP5 mutations and high bone mass had enhanced lower-body fat accumulation. Reciprocally, a low bone mineral density-associated common LRP5 allele correlated with increased abdominal adiposity. Ex vivo LRP5 expression was higher in abdominal versus gluteal adipocyte progenitors. Equivalent knockdown of LRP5 in both progenitor types dose-dependently impaired β-catenin signaling and led to distinct biological outcomes: diminished gluteal and enhanced abdominal adipogenesis. These data highlight how depot differences in WNT/β-catenin pathway activity modulate human fat distribution via effects on adipocyte progenitor biology. They also identify LRP5 as a potential pharmacologic target for the treatment of cardiometabolic disorders.
•Carriers of LRP5 variants display altered body fat distribution•LRP5 is more highly expressed in abdominal versus gluteal fat progenitor cells•LRP5 knockdown in both progenitor types leads to different biological responses•LRP5 modulates fat progenitor biology by controlling β-catenin signaling dosage
Loh et al. identify the WNT co-receptor LRP5 as a regulator of human body fat distribution, an independent predictor of diabetes and cardiovascular disease risk. Studying LRP5 gene variant carriers and human fat progenitors, they show that LRP5 differentially modulates regional adipose progenitor biology by titrating WNT/β-catenin signaling dosage.
Glucagon secretion is inhibited by glucagon-like peptide-1 (GLP-1) and stimulated by adrenaline. These opposing effects on glucagon secretion are mimicked by low (1-10 nM) and high (10 μM) concentrations of forskolin, respectively. The expression of GLP-1 receptors in α-cells is <0.2% of that in β-cells. The GLP-1-induced suppression of glucagon secretion is PKA-dependent, glucose-independent and does not involve paracrine effects mediated by insulin or somatostatin. GLP-1 is without much effect on α-cell electrical activity but selectively inhibits N-type Ca2+-channels and exocytosis. Adrenaline stimulates α-cell electrical activity, increases [Ca2+]i, enhances L-type Ca2+-channel activity and accelerates exocytosis. The stimulatory effect is partially PKA-independent and reduced in Epac2-deficient islets. We propose that GLP-1 inhibits glucagon secretion by PKA-dependent inhibition of the N-type Ca2+-channels via a small increase in intracellular cAMP ([cAMP]i). Adrenaline stimulates L-type Ca2+-channel-dependent exocytosis by activation of the low-affinity cAMP sensor Epac2 via a large increase in [cAMP]i.
An emerging view is that obesity causes metabolic problems when adipose tissue fails to meet the increased demands for fat storage. A study in this issue of Cell Metabolism (Waki et al., 2007) has identified harmine as a proadipogenic small molecule that promotes energy expenditure in white adipose tissue and delays the onset of obesity-associated diabetes.
Small-molecule ligands of nuclear hormone receptors (NHRs) govern the transcriptional regulation of metazoan development, cell differentiation, and metabolism. However, the physiological ligands of many NHRs remain poorly characterized primarily due to lack of robust analytical techniques. Using comparative metabolomics, we identified endogenous steroids that act as ligands of the C. elegans NHR, DAF-12, a vitamin-D and liver-X receptor homolog regulating larval development, fat metabolism, and lifespan. The identified molecules feature unexpected chemical modifications and include only one of two DAF-12 ligands reported earlier, necessitating a revision of previously proposed ligand biosynthetic pathways. We further show that ligand profiles are regulated by a complex enzymatic network including the Rieske oxygenase DAF-36, the short-chain dehydrogenase DHS-16, and the hydroxysteroid dehydrogenase, HSD-1. Our results demonstrate the advantages of comparative metabolomics over traditional candidate-based approaches and provide a blueprint for the identification of ligands for other C. elegans and mammalian NHRs.
Adipose tissue (AT) of obese mice and humans accumulates immune cells, which secrete cytokines that can promote insulin resistance. AT macrophages (ATMs) are thought to originate from bone marrow-derived monocytes, which infiltrate the tissue from the circulation. Here we show that a major fraction of macrophages unexpectedly undergo cell division locally within AT, as detected by Ki67 expression and 5-ethynyl-2′-deoxyuridine incorporation. Macrophages within the visceral AT (VAT), but not those in other tissues, including liver and spleen, displayed increased proliferation in obesity. Importantly, depletion of blood monocytes had no impact on ATM content, while their proliferation in situ continued. Treatment with monocyte chemotactic protein 1 (MCP-1) induced macrophage cell division in AT explants, while MCP-1 deficiency in vivo decreased ATM proliferation. These results reveal that proliferation in situ driven by MCP-1 is an important process by which macrophages accumulate in the VAT in obesity, in addition to blood monocyte recruitment.
Type 2 diabetes mellitus (T2DM) is a complex disease characterized by the inability of the insulin-producing β-cells in the endocrine pancreas to overcome insulin resistance in peripheral tissues. To determine if microRNAs are involved in the pathogenesis of human T2DM, we sequenced the small RNAs of human islets from diabetic and non-diabetic organ donors. We identified a cluster of miRNAs in an imprinted locus on human chromosome 14q32 that is highly and specifically expressed in human β-cells and dramatically down-regulated in islets from T2DM organ donors. The down-regulation of this locus strongly correlates with hyper-methylation of its promoter. Using HITS-CLIP for the essential RISC-component Argonaute, we identified disease-relevant targets of the chromosome 14q32 microRNAs, such as IAPP and TP53INP1 that cause increased β-cell apoptosis upon over-expression in human islets. Our results support a role for microRNAs and their epigenetic control by DNA methylation in the pathogenesis of T2DM.
Obesity, defined as an excessive increase in white adipose tissue (WAT), is a global health epidemic. In obesity, WAT expands by increased adipocyte size (hypertrophy) and number (hyperplasia). The location and cellular mechanisms of WAT expansion greatly affect the pathogenesis of obesity. However, the cellular and molecular mechanisms regulating adipocyte size, number and depot-dependent expansion in vivo remain largely unknown. This perspective summarizes previous work addressing adipocyte number in development and obesity and discusses recent advances in the methodologies, genetic tools, and characterization of in vivo adipocyte precursor cells allowing for directed study of hyperplastic WAT growth in vivo.
Although type-2 diabetes (T2D) is an established risk factor for hepatocellular carcinoma (HCC), the underlying mechanism that connects these two diseases is unknown. Gao et al. (2013) now suggest that nuclear receptor coactivator 5 (NCOA5) provides a genetic link between the two diseases through its effects on hepatic IL-6 expression.
Inflammation is associated with development of diseases characterized by altered nutrient metabolism. While an acute inflammatory response is host-protective and normally self-limited, chronic low-grade inflammation associated with metabolic diseases is sustained and detrimental. Resolution of inflammation involves termination of neutrophil recruitment, counter-regulation of pro-inflammatory mediators, stimulation of macrophage-mediated clearance and tissue remodeling. Specialized pro-resolving lipid mediators (SPM) -- resolvins, protectins and maresins -- are novel autacoids that resolve inflammation, protect organs, and stimulate tissue regeneration. Here, we review evidence that failure of resolution programs contributes to metabolic diseases and that SPM may play pivotal roles in their resolution.
Non-alcoholic fatty liver disease (NAFLD) affects up to 30% of the adult population in Western societies, yet the underlying molecular pathways remain poorly understood. Here, we identify the dimeric Activator Protein 1 as a regulator of NAFLD. The Fos-related antigen 1 (Fra-1) and 2 (Fra-2) prevent dietary NAFLD by inhibiting pro-steatotic PPARγ signaling. Moreover, established NAFLD and the associated liver damage can be efficiently reversed by hepatocyte-specific Fra-1 expression. In contrast, c-Fos promotes PPARγ expression, while c-Jun exerts opposing, dimer-dependent functions. Interestingly, JunD was found to be essential for PPARγ signaling and NAFLD development. This unique antagonistic regulation of PPARγ by distinct AP-1 dimers occurs at the transcriptional level and establishes AP-1 as a link between obesity, hepatic lipid metabolism and NAFLD.
NAFLD; Steatosis; Activator Protein 1; PPARγ; Lipids; Transcription
Obesity and type 2 diabetes are strongly associated with abnormal lipid metabolism and accumulation of intramyocellular triacylglycerol, but the underlying cause of these perturbations are yet unknown. Herein, we show that the lipogenic gene, stearoyl-CoA desaturase 1 (SCD1), is robustly up-regulated in skeletal muscle from extremely obese humans. High expression and activity of SCD1, an enzyme that catalyzes the synthesis of monounsaturated fatty acids, corresponded with low rates of fatty acid oxidation, increased triacylglycerol synthesis and increased monounsaturation of muscle lipids. Elevated SCD1 expression and abnormal lipid partitioning were retained in primary skeletal myocytes derived from obese compared to lean donors, implying that these traits might be driven by epigenetic and/or heritable mechanisms. Overexpression of human SCD1 in myotubes from lean subjects was sufficient to mimic the obese phenotype. These results suggest that elevated expression of SCD1 in skeletal muscle contributes to abnormal lipid metabolism and progression of obesity.
Dietary effects on tumor biology can be exploited to unravel cancer vulnerabilities. Here, we present surprising evidence for anti-proliferative action of high-calorie-diet (HCD) feeding on KRAS-driven lung tumors. Tumors of mice that commenced HCD feeding before tumor onset displayed defective unfolded protein response (UPR) and unresolved endoplasmic reticulum (ER) stress. Unresolved ER stress and reduced proliferation are reversed by chemical chaperone treatment. Whole-genome transcriptional analyses revealed FKBP10 as one of the most downregulated chaperones in tumors of the HCD-pre-tumor-onset group. FKBP10 downregulation dampens tumor growth in vitro and in vivo. Providing translational value to these results, we report that FKBP10 is expressed in human KRAS-positive and -negative lung cancers, but not in healthy parenchyma. Collectively, our data shed light on an unexpected anti-tumor action of HCD imposed before tumor onset and identify FKBP10 as a putative therapeutic target to selectively hinder lung cancer.
•HCD imposed before tumor onset inhibits KRAS-driven lung tumorigenesis•HCD imposed before tumor onset causes unresolved ER stress in lung tumors•TUDCA or PBA treatment reverses the anti-tumor action of HCD•Downregulation of the chaperone FKBP10 inhibits tumor growth
Dietary effects on tumor biology can be exploited to unravel cancer vulnerabilities. Here, Ramadori et al. exploited the surprising anti-proliferative action of high-calorie-diet feeding on KRAS-driven lung tumors to unmask the chaperone FKBP10 as a putative therapeutic target to selectively hinder lung cancer.
Given the success in engineering synthetic phenotypes in microbes and mammalian cells, constructing non-native pathways in mammals has become increasingly attractive for understanding and identifying potential targets for treating metabolic disorders. Here we introduced the glyoxylate shunt into mouse liver to investigate mammalian fatty acid metabolism. Mice expressing the shunt showed resistance to diet-induced obesity on a high fat diet despite similar food consumption. This was accompanied by a decrease in total fat mass, circulating leptin levels, plasma triglyceride concentration, and a signaling metabolite in liver, malonyl-CoA, that inhibits fatty acid degradation. Contrary to plants and bacteria, in which the glyoxylate shunt prevents the complete oxidation of fatty acids, this pathway when introduced in mice increases fatty acid oxidation such that resistance to diet-induced obesity develops. This work suggests that using non-native pathways in higher organisms to explore and modulate metabolism may be a useful approach.
Type 2 diabetes is a genetically heterogeneous disease, with several relatively rare monogenic forms and a number of more common forms resulting from a complex interaction of genetic and environmental factors. Previous studies using a candidate gene approach, family linkage studies, and gene expression profiling uncovered a number of type 2 genes, but the genetic basis of common type 2 diabetes remained unknown. Recently, a new window has opened on defining potential type 2 diabetes genes through genome-wide SNP association studies of very large populations of individuals with diabetes. This review explores the pathway leading to discovery of these genetic effects, the impact of these genetic loci on diabetes risk, the potential mechanisms of action of the genes to alter glucose homeostasis, and the limitations of these studies in defining the role of genetics in this important disease.