👤 Katherine Lawler

Obesity causes dyslipidemia and is a major risk factor for cardiovascular disease. However, the mechanisms coupling weight gain and lipid metabolism are poorly understood. Brain melanocortin 4 receptors (MC4Rs) regulate body weight and lipid metabolism in mice, but the relevance of these findings to humans is unclear. Here we investigated lipid levels in men and women with obesity due to MC4R deficiency. Among 7,719 people from the Genetics of Obesity Study cohort, we identified 316 probands and 144 adult family members with loss-of-function (LoF) MC4R mutations. Adults with MC4R deficiency had lower levels of total and low-density lipoprotein (LDL)-cholesterol and triglycerides than 336,728 controls from the UK Biobank, after adjusting for adiposity. Carriers of LoF MC4R variants within the UK Biobank had lower lipid levels and a lower risk of cardiovascular disease, after accounting for body weight, compared to noncarriers. After a high-fat meal, the postprandial rise in triglyceride-rich lipoproteins and metabolomic markers of fatty acid oxidation were reduced in people with MC4R deficiency compared to controls, changes that favor triglyceride storage in adipose tissue. We concluded that central MC4Rs regulate lipid metabolism and cardiovascular disease risk in humans, highlighting potential therapeutic approaches for cardiovascular risk reduction. Show less

Obesity is a major risk factor for many common diseases and has a substantial heritable component. To identify new genetic determinants, we performed exome-sequence analyses for adult body mass index (BMI) in up to 587,027 individuals. We identified rare loss-of-function variants in two genes (BSN and APBA1) with effects substantially larger than those of well-established obesity genes such as MC4R. In contrast to most other obesity-related genes, rare variants in BSN and APBA1 were not associated with normal variation in childhood adiposity. Furthermore, BSN protein-truncating variants (PTVs) magnified the influence of common genetic variants associated with BMI, with a common variant polygenic score exhibiting an effect twice as large in BSN PTV carriers than in noncarriers. Finally, we explored the plasma proteomic signatures of BSN PTV carriers as well as the functional consequences of BSN deletion in human induced pluripotent stem cell-derived hypothalamic neurons. Collectively, our findings implicate degenerative processes in synaptic function in the etiology of adult-onset obesity. Show less

MicroRNAs (miRNAs) modulate physiological responses by repressing the expression of gene networks. We found that global deletion of microRNA-7 (miR-7), the most enriched miRNA in the hypothalamus, causes obesity in mice. Targeted deletion of miR-7 in Single-minded homolog 1 (Sim1) neurons, a critical component of the hypothalamic melanocortin pathway, causes hyperphagia, obesity and increased linear growth, mirroring Sim1 and Melanocortin-4 receptor (MC4R) haplo-insufficiency in mice and humans. We identified Snca (α-Synuclein) and Igsf8 (Immunoglobulin Superfamily Member 8) as miR-7 target genes that act in Sim1 neurons to regulate body weight and endocrine axes. In humans, MIR-7-1 is located in the last intron of HNRNPK, whose promoter drives the expression of both genes. Genetic variants at the HNRNPK locus that reduce its expression are associated with increased height and truncal fat mass. These findings demonstrate that miR-7 suppresses gene networks involved in the hypothalamic melanocortin pathway to regulate mammalian energy homeostasis. Show less