LONP1 regulation of mitochondrial protein folding provides insight into beta cell failure in type 2 diabetes.

Proteotoxicity is a contributor to the development of type 2 diabetes (T2D), but it is unknown whether protein misfolding in T2D is generalized or has special features. Here, we report a robust accumulation of misfolded proteins within the mitochondria of human pancreatic islets in T2D and elucidate its impact on ß cell viability. Surprisingly, quantitative proteomics studies of protein aggregates reveal that human islets from donors with T2D have a signature more closely resembling mitochondrial rather than ER protein misfolding. The matrix protease LonP1 and its chaperone partner mtHSP70 were among the proteins enriched in protein aggregates. Deletion of LONP1 in mice yields mitochondrial protein misfolding and reduced respiratory function, ultimately leading to ß cell apoptosis and hyperglycemia. Intriguingly, LONP1 gain of function ameliorates mitochondrial protein misfolding and restores human ß cell survival following glucolipotoxicity via a protease-independent effect requiring LONP1-mtHSP70 chaperone activity. Thus, LONP1 promotes ß cell survival and prevents hyperglycemia by facilitating mitochondrial protein folding. These observations may open novel insights into the nature of impaired proteostasis on ß cell loss in the pathogenesis of T2D that could be considered as future therapeutic targets.

Alterations in adipose tissue distribution, cell morphology and function mark primary insulin hypersecretion in youths with obesity.

Excessive insulin secretion independent of insulin resistance, defined as primary hypersecretion, is associated with obesity and an unfavorable metabolic phenotype. We examined the characteristics of the adipose tissue in youths with primary insulin hypersecretion and the longitudinal metabolic alterations influenced by the complex adipo-insular interplay. In a multiethnic cohort of non-diabetic adolescents with obesity, primary insulin hypersecretors had enhanced model-derived ß-cell glucose sensitivity and rate sensitivity, but worse glucose tolerance, despite similar demographics, adiposity, and insulin resistance measured by both OGTT and euglycemic-hyperinsulinemic clamp. Hypersecretors had greater intrahepatic and visceral fat depots at abdominal MRI, hypertrophic abdominal subcutaneous adipocytes, higher FFA and leptin serum levels per fat mass, and faster in vivo lipid turnover assessed by a long-term 2H2O labeling protocol. At 2-year follow up, hypersecretors had greater fat accrual and 3-fold higher risk for abnormal glucose tolerance, while individuals with hypertrophic adipocytes or higher leptin levels showed enhanced ß-cell glucose sensitivity. Primary insulin hypersecretion is associated with marked alterations in adipose tissue distribution, cellularity, and lipid dynamics, independent of whole-body adiposity and insulin resistance. Pathogenetic insight into the metabolic crosstalk between ß-cell and adipocyte may help identify individuals at risk for chronic hyperinsulinemia, body weight gain, and glucose intolerance.

Variation in histone configurations correlates with gene expression across nine inbred strains of mice.

The Diversity Outbred (DO) mice and their inbred founders are widely used models of human disease. However, although the genetic diversity of these mice has been well documented, their epigenetic diversity has not. Epigenetic modifications, such as histone modifications and DNA methylation, are important regulators of gene expression and, as such, are a critical mechanistic link between genotype and phenotype. Therefore, creating a map of epigenetic modifications in the DO mice and their founders is an important step toward understanding mechanisms of gene regulation and the link to disease in this widely used resource. To this end, we performed a strain survey of epigenetic modifications in hepatocytes of the DO founders. We surveyed four histone modifications (H3K4me1, H3K4me3, H3K27me3, and H3K27ac), as well as DNA methylation. We used ChromHMM to identify 14 chromatin states, each of which represents a distinct combination of the four histone modifications. We found that the epigenetic landscape is highly variable across the DO founders and is associated with variation in gene expression across strains. We found that epigenetic state imputed into a population of DO mice recapitulated the association with gene expression seen in the founders, suggesting that both histone modifications and DNA methylation are highly heritable mechanisms of gene expression regulation. We illustrate how DO gene expression can be aligned with inbred epigenetic states to identify putative cis-regulatory regions. Finally, we provide a data resource that documents strain-specific variation in the chromatin state and DNA methylation in hepatocytes across nine widely used strains of laboratory mice.

Functional characterization of T2D-associated SNP effects on baseline and ER stress-responsive ß cell transcriptional activation.

Genome-wide association studies (GWAS) have linked single nucleotide polymorphisms (SNPs) at >250 loci in the human genome to type 2 diabetes (T2D) risk. For each locus, identifying the functional variant(s) among multiple SNPs in high linkage disequilibrium is critical to understand molecular mechanisms underlying T2D genetic risk. Using massively parallel reporter assays (MPRA), we test the cis-regulatory effects of SNPs associated with T2D and altered in vivo islet chromatin accessibility in MIN6 ß cells under steady state and pathophysiologic endoplasmic reticulum (ER) stress conditions. We identify 1,982/6,621 (29.9%) SNP-containing elements that activate transcription in MIN6 and 879 SNP alleles that modulate MPRA activity. Multiple T2D-associated SNPs alter the activity of short interspersed nuclear element (SINE)-containing elements that are strongly induced by ER stress. We identify 220 functional variants at 104 T2D association signals, narrowing 54 signals to a single candidate SNP. Together, this study identifies elements driving ß cell steady state and ER stress-responsive transcriptional activation, nominates causal T2D SNPs, and uncovers potential roles for repetitive elements in ß cell transcriptional stress response and T2D genetics.

AMULET: a novel read count-based method for effective multiplet detection from single nucleus ATAC-seq data.

Detecting multiplets in single nucleus (sn)ATAC-seq data is challenging due to data sparsity and limited dynamic range. AMULET (ATAC-seq MULtiplet Estimation Tool) enumerates regions with greater than two uniquely aligned reads across the genome to effectively detect multiplets. We evaluate the method by generating snATAC-seq data in the human blood and pancreatic islet samples. AMULET has high precision, estimated via donor-based multiplexing, and high recall, estimated via simulated multiplets, compared to alternatives and identifies multiplets most effectively when a certain read depth of 25K median valid reads per nucleus is achieved.

Tet2 Controls the Responses of ß cells to Inflammation in Autoimmune Diabetes.

ß cells may participate and contribute to their own demise during Type 1 diabetes (T1D). Here we report a role of their expression of Tet2 in regulating immune killing. Tet2 is induced in murine and human ß cells with inflammation but its expression is reduced in surviving ß cells. Tet2-KO mice that receive WT bone marrow transplants develop insulitis but not diabetes and islet infiltrates do not eliminate ß cells even though immune cells from the mice can transfer diabetes to NOD/scid recipients. Tet2-KO recipients are protected from transfer of disease by diabetogenic immune cells.Tet2-KO ß cells show reduced expression of IFNγ-induced inflammatory genes that are needed to activate diabetogenic T cells. Here we show that Tet2 regulates pathologic interactions between ß cells and immune cells and controls damaging inflammatory pathways. Our data suggests that eliminating TET2 in ß cells may reduce activating pathologic immune cells and killing of ß cells.

Altered In Vivo Lipid Fluxes and Cell Dynamics in Subcutaneous Adipose Tissues Are Associated With the Unfavorable Pattern of Fat Distribution in Obese Adolescent Girls.

Patterns of abdominal fat distribution (for example, a high vs. low visceral adipose tissue [VAT]/[VAT + subcutaneous adipose tissue (SAT)] ratio), independent of obesity, during adolescence carry a high risk for insulin resistance and type 2 diabetes. Longitudinal follow-up of a cohort of obese adolescents has recently revealed that a high ratio (high VAT/[VAT + SAT]) is a major determinant of fatty liver and metabolic impairment over time, with these effects being more pronounced in girls than in boys. To unravel the underlying metabolic alterations associated with the unfavorable VAT/(VAT + SAT) phenotype, we used the 2H2O labeling method to measure the turnover of adipose lipids and cells in the subcutaneous abdominal and gluteal/femoral adipose tissue (SAT) of weight-stable obese adolescent girls with a similar level of obesity but discordant VAT/(VAT + SAT) ratios. Girls with the unfavorable (high VAT/[VAT + SAT]) phenotype exhibited higher in vivo rates of triglyceride (TG) turnover (representing both lipolysis and synthesis at steady state), without significant differences in de novo lipogenesis in both abdominal and gluteal depots, compared with obese girls with the favorable phenotype. Moreover, mature adipocytes had higher turnover, with no difference in stromal vascular cell proliferation in both depots in the metabolically unfavorable phenotype. The higher TG turnover rates were significantly correlated with higher intrahepatic fat stores. These findings are contrary to the hypothesis that impaired capacity to deposit TGs or proliferation of new mature adipocytes are potential mechanisms for ectopic fat distribution in this setting. In summary, these results suggest that increased turnover of TGs (lipolysis) and of mature adipocytes in both abdominal and gluteal SAT may contribute to metabolic impairment and the development of fatty liver, even at this very early stage of disease.

Multiomic Profiling Identifies cis-Regulatory Networks Underlying Human Pancreatic ß Cell Identity and Function.

EndoC-ßH1 is emerging as a critical human ß cell model to study the genetic and environmental etiologies of ß cell (dys)function and diabetes. Comprehensive knowledge of its molecular landscape is lacking, yet required, for effective use of this model. Here, we report chromosomal (spectral karyotyping), genetic (genotyping), epigenomic (ChIP-seq and ATAC-seq), chromatin interaction (Hi-C and Pol2 ChIA-PET), and transcriptomic (RNA-seq and miRNA-seq) maps of EndoC-ßH1. Analyses of these maps define known (e.g., PDX1 and ISL1) and putative (e.g., PCSK1 and mir-375) ß cell-specific transcriptional cis-regulatory networks and identify allelic effects on cis-regulatory element use. Importantly, comparison with maps generated in primary human islets and/or ß cells indicates preservation of chromatin looping but also highlights chromosomal aberrations and fetal genomic signatures in EndoC-ßH1. Together, these maps, and a web application we created for their exploration, provide important tools for the design of experiments to probe and manipulate the genetic programs governing ß cell identity and (dys)function in diabetes.

Type 2 Diabetes-Associated Genetic Variants Regulate Chromatin Accessibility in Human Islets.

Type 2 diabetes (T2D) is a complex disorder in which both genetic and environmental risk factors contribute to islet dysfunction and failure. Genome-wide association studies (GWAS) have linked single nucleotide polymorphisms (SNPs), most of which are noncoding, in >200 loci to islet dysfunction and T2D. Identification of the putative causal variants and their target genes and whether they lead to gain or loss of function remains challenging. Here, we profiled chromatin accessibility in pancreatic islet samples from 19 genotyped individuals and identified 2,949 SNPs associated with in vivo cis-regulatory element use (i.e., chromatin accessibility quantitative trait loci [caQTL]). Among the caQTLs tested (n = 13) using luciferase reporter assays in MIN6 ß-cells, more than half exhibited effects on enhancer activity that were consistent with in vivo chromatin accessibility changes. Importantly, islet caQTL analysis nominated putative causal SNPs in 13 T2D-associated GWAS loci, linking 7 and 6 T2D risk alleles, respectively, to gain or loss of in vivo chromatin accessibility. By investigating the effect of genetic variants on chromatin accessibility in islets, this study is an important step forward in translating T2D-associated GWAS SNP into functional molecular consequences.

A Common Type 2 Diabetes Risk Variant Potentiates Activity of an Evolutionarily Conserved Islet Stretch Enhancer and Increases C2CD4A and C2CD4B Expression.

Genome-wide association studies (GWASs) and functional genomics approaches implicate enhancer disruption in islet dysfunction and type 2 diabetes (T2D) risk. We applied genetic fine-mapping and functional (epi)genomic approaches to a T2D- and proinsulin-associated 15q22.2 locus to identify a most likely causal variant, determine its direction of effect, and elucidate plausible target genes. Fine-mapping and conditional analyses of proinsulin levels of 8,635 non-diabetic individuals from the METSIM study support a single association signal represented by a cluster of 16 strongly associated (p < 10-17) variants in high linkage disequilibrium (r2 > 0.8) with the GWAS index SNP rs7172432. These variants reside in an evolutionarily and functionally conserved islet and ß cell stretch or super enhancer; the most strongly associated variant (rs7163757, p = 3 × 10-19) overlaps a conserved islet open chromatin site. DNA sequence containing the rs7163757 risk allele displayed 2-fold higher enhancer activity than the non-risk allele in reporter assays (p < 0.01) and was differentially bound by ß cell nuclear extract proteins. Transcription factor NFAT specifically potentiated risk-allele enhancer activity and altered patterns of nuclear protein binding to the risk allele in vitro, suggesting that it could be a factor mediating risk-allele effects. Finally, the rs7163757 proinsulin-raising and T2D risk allele (C) was associated with increased expression of C2CD4B, and possibly C2CD4A, both of which were induced by inflammatory cytokines, in human islets. Together, these data suggest that rs7163757 contributes to genetic risk of islet dysfunction and T2D by increasing NFAT-mediated islet enhancer activity and modulating C2CD4B, and possibly C2CD4A, expression in (patho)physiologic states.

The "adipose tissue expandability" hypothesis: a potential mechanism for insulin resistance in obese youth.

Obesity has become a major global health challenge of the 21st century, as it is associated with the onset of type 2 diabetes (T2D) and cardiovascular complications, even at a very early age in life. The root causes of pediatric obesity remain incompletely understood. The obesity epidemic together with the relationship of obesity to the growing population burden of chronic disease presents unprecedented research opportunities and challenges. Decades of obesity-related research funded by governments around the world have yielded many important discoveries about both etiological pathways and preventive or therapeutic interventions. Yet, there is a sense that the problem is outpacing these research efforts. Obesity poses a significant risk for the development of cardiovascular disease (CVD) , diabetes and certain cancers thereby shortening life expectancy. Nevertheless, many obese individuals do not develop any of these comorbidities. One hypothesis explaining this dilemma is that total body fat is not the culprit of adverse health in obesity rather the relative proportion of lipids in various fat depots is what determines the metabolic risk. In this review, we describe the role of altered fat partitioning in youth onset obesity and its relation to fatty liver and T2D during adolescence.

Alpha TC1 and Beta-TC-6 genomic profiling uncovers both shared and distinct transcriptional regulatory features with their primary islet counterparts.

Alpha TC1 (αTC1) and Beta-TC-6 (ßTC6) mouse islet cell lines are cellular models of islet (dys)function and type 2 diabetes (T2D). However, genomic characteristics of these cells, and their similarities to primary islet alpha and beta cells, are undefined. Here, we report the epigenomic (ATAC-seq) and transcriptomic (RNA-seq) landscapes of αTC1 and ßTC6 cells. Each cell type exhibits hallmarks of its primary islet cell counterpart including cell-specific expression of beta (e.g., Pdx1) and alpha (e.g., Arx) cell transcription factors (TFs), and enrichment of binding motifs for these TFs in αTC1/ßTC6 cis-regulatory elements. αTC1/ßTC6 transcriptomes overlap significantly with the transcriptomes of primary mouse/human alpha and beta cells. Our data further indicate that ATAC-seq detects cell-specific regulatory elements for cell types comprising ≥ 20% of a mixed cell population. We identified αTC1/ßTC6 cis-regulatory elements orthologous to those containing type 2 diabetes (T2D)-associated SNPs in human islets for 33 loci, suggesting these cells' utility to dissect T2D molecular genetics in these regions. Together, these maps provide important insights into the conserved regulatory architecture between αTC1/ßTC6 and primary islet cells that can be leveraged in functional (epi)genomic approaches to dissect the genetic and molecular factors controlling islet cell identity and function.

A Type 2 Diabetes-Associated Functional Regulatory Variant in a Pancreatic Islet Enhancer at the ADCY5 Locus.

Molecular mechanisms remain unknown for most type 2 diabetes genome-wide association study identified loci. Variants associated with type 2 diabetes and fasting glucose levels reside in introns of ADCY5, a gene that encodes adenylate cyclase 5. Adenylate cyclase 5 catalyzes the production of cyclic AMP, which is a second messenger molecule involved in cell signaling and pancreatic ß-cell insulin secretion. We demonstrated that type 2 diabetes risk alleles are associated with decreased ADCY5 expression in human islets and examined candidate variants for regulatory function. rs11708067 overlaps a predicted enhancer region in pancreatic islets. The type 2 diabetes risk rs11708067-A allele showed fewer H3K27ac ChIP-seq reads in human islets, lower transcriptional activity in reporter assays in rodent ß-cells (rat 832/13 and mouse MIN6), and increased nuclear protein binding compared with the rs11708067-G allele. Homozygous deletion of the orthologous enhancer region in 832/13 cells resulted in a 64% reduction in expression level of Adcy5, but not adjacent gene Sec22a, and a 39% reduction in insulin secretion. Together, these data suggest that rs11708067-A risk allele contributes to type 2 diabetes by disrupting an islet enhancer, which results in reduced ADCY5 expression and impaired insulin secretion.

The rs7903146 Variant in the TCF7L2 Gene Increases the Risk of Prediabetes/Type 2 Diabetes in Obese Adolescents by Impairing ß-Cell Function and Hepatic Insulin Sensitivity.

OBJECTIVE: In this study, we aimed to explore the mechanism by which TCF7L2 rs7903146 risk allele confers susceptibility to impaired glucose tolerance (IGT) or type 2 diabetes (T2D) in obese adolescents. RESEARCH DESIGN AND METHODS: The rs7903146 variant in the TCF7L2 gene was genotyped in a multiethnic cohort of 955 youths. All subjects underwent an oral glucose tolerance test with the use of the Oral Minimal Model to assess insulin secretion, and 33 subjects underwent a hyperinsulinemic-euglycemic clamp. In 307 subjects, a follow-up oral glucose tolerance test was repeated after 3.11 ± 2.36 years. RESULTS: The TCF7L2 rs7903146 risk allele was associated with higher 2-h glucose levels in Caucasians (P = 0.006) and African Americans (P = 0.009), and a trend was seen also in Hispanics (P = 0.072). Also, the T allele was associated with decreased ß-cell responsivity and IGT (P < 0.05). Suppression of endogenous hepatic glucose production was lower in subjects with the risk variant (P = 0.006). Finally, the odds of showing IGT/T2D at follow-up were higher in subjects carrying the minor allele (odds ratio 2.224; 95% CI 1.370-3.612; P = 0.0012). CONCLUSIONS: The rs7903146 variant in the TCF7L2 gene increases the risk of IGT/T2D in obese adolescents by impairing ß-cell function, and hepatic insulin sensitivity predicts the development of IGT/T2D over time.

Adolescent Obesity and Insulin Resistance: Roles of Ectopic Fat Accumulation and Adipose Inflammation.

As a consequence of the global rise in the prevalence of adolescent obesity, an unprecedented phenomenon of type 2 diabetes has emerged in pediatrics. At the heart of the development of type 2 diabetes lies a key metabolic derangement: insulin resistance (IR). Despite the widespread occurrence of IR affecting an unmeasurable number of youths worldwide, its pathogenesis remains elusive. IR in obese youth is a complex phenomenon that defies explanation by a single pathway. In this review we first describe recent data on the prevalence, severity, and racial/ethnic differences in pediatric obesity. We follow by elucidating the initiating events associated with the onset of IR, and describe a distinct "endophenotype" in obese adolescents characterized by a thin superficial layer of abdominal subcutaneous adipose tissue, increased visceral adipose tissue, marked IR, dyslipidemia, and fatty liver. Further, we provide evidence for the cellular and molecular mechanisms associated with this peculiar endophenotype and its relations to IR in the obese adolescent.

Genetic regulatory signatures underlying islet gene expression and type 2 diabetes.

Genome-wide association studies (GWAS) have identified >100 independent SNPs that modulate the risk of type 2 diabetes (T2D) and related traits. However, the pathogenic mechanisms of most of these SNPs remain elusive. Here, we examined genomic, epigenomic, and transcriptomic profiles in human pancreatic islets to understand the links between genetic variation, chromatin landscape, and gene expression in the context of T2D. We first integrated genome and transcriptome variation across 112 islet samples to produce dense cis-expression quantitative trait loci (cis-eQTL) maps. Additional integration with chromatin-state maps for islets and other diverse tissue types revealed that cis-eQTLs for islet-specific genes are specifically and significantly enriched in islet stretch enhancers. High-resolution chromatin accessibility profiling using assay for transposase-accessible chromatin sequencing (ATAC-seq) in two islet samples enabled us to identify specific transcription factor (TF) footprints embedded in active regulatory elements, which are highly enriched for islet cis-eQTL. Aggregate allelic bias signatures in TF footprints enabled us de novo to reconstruct TF binding affinities genetically, which support the high-quality nature of the TF footprint predictions. Interestingly, we found that T2D GWAS loci were strikingly and specifically enriched in islet Regulatory Factor X (RFX) footprints. Remarkably, within and across independent loci, T2D risk alleles that overlap with RFX footprints uniformly disrupt the RFX motifs at high-information content positions. Together, these results suggest that common regulatory variations have shaped islet TF footprints and the transcriptome and that a confluent RFX regulatory grammar plays a significant role in the genetic component of T2D predisposition.

Single-cell transcriptomes identify human islet cell signatures and reveal cell-type-specific expression changes in type 2 diabetes.

Blood glucose levels are tightly controlled by the coordinated action of at least four cell types constituting pancreatic islets. Changes in the proportion and/or function of these cells are associated with genetic and molecular pathophysiology of monogenic, type 1, and type 2 (T2D) diabetes. Cellular heterogeneity impedes precise understanding of the molecular components of each islet cell type that govern islet (dys)function, particularly the less abundant delta and gamma/pancreatic polypeptide (PP) cells. Here, we report single-cell transcriptomes for 638 cells from nondiabetic (ND) and T2D human islet samples. Analyses of ND single-cell transcriptomes identified distinct alpha, beta, delta, and PP/gamma cell-type signatures. Genes linked to rare and common forms of islet dysfunction and diabetes were expressed in the delta and PP/gamma cell types. Moreover, this study revealed that delta cells specifically express receptors that receive and coordinate systemic cues from the leptin, ghrelin, and dopamine signaling pathways implicating them as integrators of central and peripheral metabolic signals into the pancreatic islet. Finally, single-cell transcriptome profiling revealed genes differentially regulated between T2D and ND alpha, beta, and delta cells that were undetectable in paired whole islet analyses. This study thus identifies fundamental cell-type-specific features of pancreatic islet (dys)function and provides a critical resource for comprehensive understanding of islet biology and diabetes pathogenesis.

MARCH1 regulates insulin sensitivity by controlling cell surface insulin receptor levels.

Insulin resistance is a key driver of type 2 diabetes (T2D) and is characterized by defective insulin receptor (INSR) signalling. Although surface INSR downregulation is a well-established contributor to insulin resistance, the underlying molecular mechanisms remain obscure. Here we show that the E3 ubiquitin ligase MARCH1 impairs cellular insulin action by degrading cell surface INSR. Using a large-scale RNA interference screen, we identify MARCH1 as a negative regulator of INSR signalling. March1 loss-of-function enhances, and March1 overexpression impairs, hepatic insulin sensitivity in mice. MARCH1 ubiquitinates INSR to decrease cell surface INSR levels, but unlike other INSR ubiquitin ligases, MARCH1 acts in the basal state rather than after insulin stimulation. Thus, MARCH1 may help set the basal gain of insulin signalling. MARCH1 expression is increased in white adipose tissue of obese humans, suggesting that MARCH1 contributes to the pathophysiology of T2D and could be a new therapeutic target.

A Role of the Inflammasome in the Low Storage Capacity of the Abdominal Subcutaneous Adipose Tissue in Obese Adolescents.

The innate immune cell sensor leucine-rich-containing family, pyrin domain containing 3 (NLRP3) inflammasome controls the activation of caspase-1, and the release of proinflammatory cytokines interleukin (IL)-1ß and IL-18. The NLRP3 inflammasome is implicated in adipose tissue inflammation and the pathogenesis of insulin resistance. Herein, we tested the hypothesis that adipose tissue inflammation and NLRP3 inflammasome are linked to the downregulation of subcutaneous adipose tissue (SAT) adipogenesis/lipogenesis in obese adolescents with altered abdominal fat partitioning. We performed abdominal SAT biopsies on 58 obese adolescents and grouped them by MRI-derived visceral fat to visceral adipose tissue (VAT) plus SAT (VAT/VAT+SAT) ratio (cutoff 0.11). Adolescents with a high VAT/VAT+SAT ratio showed higher SAT macrophage infiltration and higher expression of the NLRP3 inflammasome-related genes (i.e., TLR4, NLRP3, IL1B, and CASP1). The increase in inflammation markers was paralleled by a decrease in genes related to insulin sensitivity (ADIPOQ, GLUT4, PPARG2, and SIRT1) and lipogenesis (SREBP1c, ACC, LPL, and FASN). Furthermore, SAT ceramide concentrations correlated with the expression of CASP1 and IL1B. Infiltration of macrophages and upregulation of the NLRP3 inflammasome together with the associated high ceramide content in the plasma and SAT of obese adolescents with a high VAT/VAT+SAT may contribute to the limited expansion of the subcutaneous abdominal adipose depot and the development of insulin resistance.

Caspase-12, but Not Caspase-11, Inhibits Obesity and Insulin Resistance.

Inflammation is well established to significantly impact metabolic diseases. The inflammatory protease caspase-1 has been implicated in metabolic dysfunction; however, a potential role for the related inflammatory caspases is currently unknown. In this study, we investigated a role for caspase-11 and caspase-12 in obesity and insulin resistance. Loss of caspase-12 in two independently generated mouse strains predisposed mice to develop obesity, metabolic inflammation, and insulin resistance, whereas loss of caspase-11 had no effect. The use of bone marrow chimeras determined that deletion of caspase-12 in the radio-resistant compartment was responsible for this metabolic phenotype. The Nlrp3 inflammasome pathway mediated the metabolic syndrome of caspase-12-deficient mice as ablation of Nlrp3 reversed Casp12(-/-) mice obesity phenotype. Although the majority of people lack a functional caspase-12 because of a T(125) single nucleotide polymorphism that introduces a premature stop codon, a fraction of African descendents express full-length caspase-12. Expression of caspase-12 was linked to decreased systemic and adipose tissue inflammation in a cohort of African American obese children. However, analysis of the Dallas Heart Study African American cohort indicated that the coding T(125)C single nucleotide polymorphism was not associated with metabolic parameters in humans, suggesting that host-specific differences mediate the expressivity of metabolic disease.