Genetics of Obesity and Type 2 Diabetes

Abstract

The modern generalization of sedentary life and caloric abundance has created new physiological conditions capable of changing the level of expression of a number of genes involved in fuel metabolism and body weight regulation. It is likely that the genetic variants or alleles of these genes have in the past participated in the adaptation of human physiology to its evolutionary constraints. The nature and prevalence of polymorphisms responsible for the quantitative variation of complex metabolic traits may have been different among human populations, depending on their environment and ancestral genetic background. These polymorphisms could likely explain differences in disease susceptibility and prevalence among groups of humans. From complex traits to potentially complex alleles, understanding the molecular genetic basis underlying quantitative variation will continue to be a growing concern among geneticists dealing with obesity and type 2 diabetes, the main fuel disorders of the modern era. Genomics and genetic epidemiology now allow highlevel linkage and association studies to be designed. But the pooling of large trans-geographic cohorts may in fact increase the genetic heterogeneity of studied traits and dilute genotype-phenotype associations. In this article, we underscore the importance of selecting the traits to be subjected to quantitative genetic analysis. Although this is not possible for most other multifactorial diseases, obesity and type 2 diabetes can be subjected to a pregenetic dissection of complexity into simpler quantitative traits (QTs). This dissection is based on the pathogenic mechanisms, and the time course of the traits, and the individuals' age, within the predisease period rather than on descriptive parameters after disease diagnosis. We defend that this approach of phenotypes may ease future associations to be established between QTs of intermediate complexity and genetic polymorphisms. Diabetes 51 (Suppl. 3): S295-S303, 2002

Basic and Genetic Aspects of Food Intake Control and Obesity: Role of Dopamin Receptor D2 TaqIA Polymorphism

“…In addition, genes described in monogenic forms of obesity have been investigated for a possible role in the common obesity genesis. 6 However, replication of most results has been somehow inconsistent, and so the findings of candidate gene studies remain obscure.…”

“…18 In addition, there may be mutations in genes affecting the hypothalamus development and therefore, promoting obesity. 6 It is also important to note that obesity may be a central component of several pleiotropic syndromes, such as Alstrom, Albright, Pader-Willi, BardetBiedel, Fragile X, among other syndromes. 17 In complex diseases such as common obesity, it is GI, gastrointestinal; GRP, gastrin-releasing peptide; CCK, cholecystokinin; PYY, peptide YY; GLP1: glucagon-like peptide-1; ApoAIV, apolipoprotein AIV; CART, cocaine and amphetamine-regulated transcript; POMC, proopiomelanocortin; α-MSH, alpha-melanocyte-stimulating hormone; NPY: neuropeptide Y; AgRP, agouti-related protein.…”

“…On the other hand, binding of AgRP to MC4R promotes increased intake. 2,6 Leptin activates the POMC neurons and inhibits AgRP neurons. 2,6,7 A scheme on the interaction of homeostatic intake control is depicted in Figure 2.…”

“…These studies are based on the association of several markers, usually SNP and the approach is particularly useful in common complex diseases, such as obesity and diabetes. 6 The latest update of "the human obesity gene map", performed by Rankinen and co-workers associated obesity with 253 loci after analysis of 61 GWAS. 33 The number of associations between SNPs and obesity has 127 candidate genes described, and of these, 22 genes are supported by more than five studies.…”

Obesity and the development of type 2 diabetes: the effects of fatty tissue inflammation

“…To identify specific gene defects, Bougnères describes the need to phenotype obesity and DM in order to better identify small genetic variants, as the expression of polymorphisms may be related to environmental changes or triggers that lead to susceptibility to DM and obesity as opposed to monogenic abnormalities. 19 In this regard, environment plays a key role in genetic expression, minimizing the ability to target specific genes for therapy.…”