Functional validation of human rare missense variants associated with body fat distribution and cardiometabolic risk
type: CreativeWork
description: Body fat distribution is a predictor of metabolic and cardiovascular disease independent of body mass index (BMI) and is heritable. To understand the genetic determinants of the differences observed in fat distribution in the general population, genome-wide association studies (GWAS) have emerged as an extremely useful approach and have convincingly associated many single nucleotide polymorphisms (SNPs) with body fat distribution. Unfortunately, it has proven very difficult to link specific genes or genetic variants with these findings, reducing their translational impact. However, massive increases in the size of human genetic studies have increased the power of studies to confidently link rare missense (coding) variants with a range of phenotypes. In collaboration with colleagues in the MRC Epidemiology Unit in Cambridge, we recently identified rare missense variants in ALK7 (p.I195T and p.N150H), CALCRL (p.L87P), PLIN1 (p.L90P) and PDE3B (p.R783X) which were associated with a favourable body fat distribution and with protection from cardiometabolic disease, while a variant in gene PNPLA2 (p.N252K) was associated with an adverse phenotype (1). To understand the roles of these genes, initial loss-of-function studies were carried out using siRNA-mediated knockdown in 3T3-L1 (pre)adipocytes, as all the genes are expressed in adipose tissue and have been at least loosely implicated in the regulation of intracellular lipolysis. In this cell model, Plin1 depletion resulted in an increase in basal lipolysis while isoproterenol stimulated lipolysis was suppressed. Pnpla2 depletion, on the other hand, impaired lipolysis under both basal and stimulated conditions. Alk7 or Calcrl knockdown resulted in a consistent decrease in lipolysis while the impact on adipogenesis was variable. Depletion of Pde3b did not have any impact on adipogenesis or lipolysis. Subsequent studies focussed on functional analysis of a subset of the specific missense variants. mRNA expression of the PN…
abstract: Body fat distribution is a predictor of metabolic and cardiovascular disease independent of body mass index (BMI) and is heritable. To understand the genetic determinants of the differences observed in fat distribution in the general population, genome-wide association studies (GWAS) have emerged as an extremely useful approach and have convincingly associated many single nucleotide polymorphisms (SNPs) with body fat distribution. Unfortunately, it has proven very difficult to link specific genes or genetic variants with these findings, reducing their translational impact. However, massive increases in the size of human genetic studies have increased the power of studies to confidently link rare missense (coding) variants with a range of phenotypes. In collaboration with colleagues in the MRC Epidemiology Unit in Cambridge, we recently identified rare missense variants in ALK7 (p.I195T and p.N150H), CALCRL (p.L87P), PLIN1 (p.L90P) and PDE3B (p.R783X) which were associated with a favourable body fat distribution and with protection from cardiometabolic disease, while a variant in gene PNPLA2 (p.N252K) was associated with an adverse phenotype (1). To understand the roles of these genes, initial loss-of-function studies were carried out using siRNA-mediated knockdown in 3T3-L1 (pre)adipocytes, as all the genes are expressed in adipose tissue and have been at least loosely implicated in the regulation of intracellular lipolysis. In this cell model, Plin1 depletion resulted in an increase in basal lipolysis while isoproterenol stimulated lipolysis was suppressed. Pnpla2 depletion, on the other hand, impaired lipolysis under both basal and stimulated conditions. Alk7 or Calcrl knockdown resulted in a consistent decrease in lipolysis while the impact on adipogenesis was variable. Depletion of Pde3b did not have any impact on adipogenesis or lipolysis. Subsequent studies focussed on functional analysis of a subset of the specific missense variants. mRNA expression of the PN…
author: Dong, Liang
language: eng
keywords: white adipose tissue, adipogenesis, lipolysis, lipid droplet, body fat distribution, genetic variants, activin receptor type-1C, calcitonin gene-related peptide type 1 receptor, perilipin 1, phosphodiesterase 3B, adipose triglyceride lipase
license: https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/a747eafd-f9a2-4961-9594-7f1d790d505b/download
license: https://www.rioxx.net/licenses/all-rights-reserved/
date published: 2021-04-01
date modified: 2026-07-22T22:24:04Z
provider: Cambridge University
publisher: Networked Digital Library of Theses and Dissertations
type: WebPage
source organization: University of Cambridge

PropertyValue
property ID: DOI
value: 10.17863/CAM.77250