Integrative genomic analysis implicates limited peripheral adipose storage capacity in the pathogenesis of human insulin resistance

Abstract

Insulin resistance is a key mediator of obesity-related cardiometabolic disease, yet the mechanisms underlying this link remain obscure. Using an integrative genomic approach, we identify 53 genomic regions associated with insulin resistance phenotypes (higher fasting insulin adjusted for BMI, lower HDL cholesterol and higher triglycerides) and provide evidence that their link with higher cardiometabolic risk is underpinned by an association with lower adipose mass in peripheral compartments. Using these 53 loci, we show a polygenic contribution to familial partial lipodystrophy-type 1, a severe form of insulin resistance, and highlight shared molecular mechanisms between common/mild and rare/severe insulin resistance. Population-level genetic analyses combined with experiments in cellular models implicate CCDC92, DNAH10 and L3MBTL3 as previously unrecognised molecules influencing adipocyte differentiation. Our findings support the notion that limited storage capacity of peripheral adipose tissue is an important aetiological component in insulin-resistant cardiometabolic disease and highlight genes and mechanisms underpinning this link.

Muscle and adipose tissue insulin resistance: malady without mechanism?

“…Indeed, genetic lipodystrophies, characterized by prominent central adiposity, dyslipidemia and hepatic steatosis, closely mimic common insulin resistance (34) while drugs such as thiazolidinediones that increase adipose tissue lipid storage capacity improve whole body insulin sensitivity. This supports the notion, as suggested by others, that insulin resistance ensues from an inability to safely quarantine lipid in adipose tissue stores (113).…”

PNPLA3 and obesity: a synergistic relationship in NAFLD

“…This point is illustrated by rare monogenic lipodystrophy, elegant animal models and common genetic variants that impair adipose expansion 7 . Thus, the high BMI categories in this study comprise individuals who have 'full' adipose stores, in whom the positive energy balance is directed to the liver, where polymorphisms can trigger lipotoxicity.…”

Angptl8 antisense oligonucleotide improves adipose lipid metabolism and prevents diet-induced NAFLD and hepatic insulin resistance in rodents

“…This phenotypic heterogeneity may lie in differences in adipose biology [1]. Notably, some genes linked to forms of lipodystrophy are also dysregulated in individuals with more common forms of insulin resistance [2], lending genetic support for a key role for adipose dysfunction in individuals who develop insulin resistance [3]. Thiazolidinediones (TZDs) are the only medications currently available that improve adipose function.…”