FTO—the first GWAS-identified obesity gene

The bigger picture of FTO—the first GWAS-identified obesity gene
Nature Reviews Endocrinology  10, 51–61 (2014)
Ruth J. F. Loos & Giles S. H. Yeo
http://www.nature.com/nrendo/journal/v10/n1/full/nrendo.2013.227.html

Single nucleotide polymorphisms (SNPs) that cluster in the first intron of fat mass and obesity associated (FTO) gene are associated obesity traits in genome-wide association studies.
The minor allele increases BMI by 0.39 kg/m2 (or 1,130 g in body weight) and risk of obesity by 1.20-fold.
This association has been confirmed across age groups and populations of diverse ancestry; the largest effect is seen in young adulthood.
The effect of FTO SNPs on obesity traits in populations of African and Asian ancestry is similar or somewhat smaller than in European ancestry populations.
However, the BMI-increasing allele in FTO is substantially less prevalent in populations with non-European ancestry.
FTO SNPs do not influence physical activity levels; yet, in physically active individuals, FTO’s effect on obesity susceptibility is attenuated by approximately 30%.
Evidence from epidemiological and functional studies suggests that FTO confers an increased risk of obesity by subtly changing food intake and preference.
Moreover, emerging data suggest a role for FTO in nutrient sensing, regulation of mRNA translation and general growth.
In this Review, we discuss the genetic epidemiology of FTO and discuss how its complex biology might link to the regulation of body weight.

Mitochondrial allostatic load

Mitochondrial allostatic load puts the ‘gluc’ back in glucocorticoids
Nature Reviews Endocrinology  10, 303–310 (2014)
Martin Picard, et al.
http://www.nature.com/nrendo/journal/v10/n5/full/nrendo.2014.22.html

The link between chronic psychosocial [stress] and metabolic stress and the pathogenesis of disease has been extensively documented.
Nevertheless, the cellular mechanisms by which stressful life experiences and their associated primary neuroendocrine mediators cause biological damage and increase disease risk remain poorly understood.

The allostatic load model of chronic stress focuses on glucocorticoid dysregulation.
In this Perspectives, we expand upon the metabolic aspects of this model—particularly glucose imbalance—and propose that mitochondrial dysfunction constitutes an early, modifiable target of chronic stress and stress-related health behaviours.
Central to this process is mitochondrial regulation of energy metabolism and cellular signalling.
Chronically elevated glucose levels damage both mitochondria and mitochondrial DNA, generating toxic products that can promote systemic inflammation, alter gene expression and hasten cell ageing.
Consequently, the concept of ‘mitochondrial allostatic load’ defines the deleterious structural and functional changes that mitochondria undergo in response to elevated glucose levels and stress-related pathophysiology.