TY - JOUR

T1 - Genes that make you fat, but keep you healthy

AU - Loos, Ruth J.F.

AU - Kilpeläinen, T.O.

N1 - This article is protected by copyright. All rights reserved.

PY - 2018

Y1 - 2018

N2 - Obesity prevalence continues to rise worldwide, posing a substantial burden on people's health. However, up to 45% of obese individuals do not suffer from cardiometabolic complications, also called the metabolically healthy obese (MHO). Concurrently, up to 30% of normal weight individuals demonstrate cardiometabolic risk factors that are generally observed in obese individuals; the metabolically obese normal weight (MONW). Besides lifestyle, environmental factors and demographic factors, innate biological mechanisms are known to contribute to the etiology of the MHO and MONW phenotypes, as well. Experimental studies in animal models have shown that adipose tissue expandability, fat distribution, adipogenesis, adipose tissue vascularization, inflammation and fibrosis, and mitochondrial function are the main mechanisms that uncouple adiposity from its cardiometabolic comorbidities. We reviewed current genetic association studies to expand insights into the biology of MHO/MONW phenotypes. At least four genetic loci were identified through genome-wide association studies for body fat percentage (BF%) of which the BF%-increasing allele was associated with a protective effect on glycemic and lipid outcomes. For some, this association was mediated through favorable effects on body fat distribution. Other studies that characterized the genetic susceptibility of insulin resistance, found that a higher susceptibility was associated with lower overall adiposity due to less fat accumulation at hips and legs, suggesting that an impaired capacity to store fat subcutaneously or a preferential storage in the intra-abdominal cavity may be metabolically harmful. Clearly, more work remains to be done in this field, first through gene discovery, and subsequently through functional follow-up of identified genes. This article is protected by copyright. All rights reserved.

AB - Obesity prevalence continues to rise worldwide, posing a substantial burden on people's health. However, up to 45% of obese individuals do not suffer from cardiometabolic complications, also called the metabolically healthy obese (MHO). Concurrently, up to 30% of normal weight individuals demonstrate cardiometabolic risk factors that are generally observed in obese individuals; the metabolically obese normal weight (MONW). Besides lifestyle, environmental factors and demographic factors, innate biological mechanisms are known to contribute to the etiology of the MHO and MONW phenotypes, as well. Experimental studies in animal models have shown that adipose tissue expandability, fat distribution, adipogenesis, adipose tissue vascularization, inflammation and fibrosis, and mitochondrial function are the main mechanisms that uncouple adiposity from its cardiometabolic comorbidities. We reviewed current genetic association studies to expand insights into the biology of MHO/MONW phenotypes. At least four genetic loci were identified through genome-wide association studies for body fat percentage (BF%) of which the BF%-increasing allele was associated with a protective effect on glycemic and lipid outcomes. For some, this association was mediated through favorable effects on body fat distribution. Other studies that characterized the genetic susceptibility of insulin resistance, found that a higher susceptibility was associated with lower overall adiposity due to less fat accumulation at hips and legs, suggesting that an impaired capacity to store fat subcutaneously or a preferential storage in the intra-abdominal cavity may be metabolically harmful. Clearly, more work remains to be done in this field, first through gene discovery, and subsequently through functional follow-up of identified genes. This article is protected by copyright. All rights reserved.

KW - cardiovascular risk factors

KW - diabetes

KW - epidemiology

KW - genetics

KW - metabolism & endocrinology

U2 - 10.1111/joim.12827

DO - 10.1111/joim.12827

M3 - Journal article

C2 - 30144199

VL - 284

SP - 450

EP - 463

JO - Journal of Internal Medicine

JF - Journal of Internal Medicine

SN - 0955-7873

IS - 5

ER -