Insulin resistance and low metabolic rate: do they cause obesity?

Insulin resistance and obesity have genetic determinants which are separate and probably polygenic. Under certain environmental conditions, both probably offer selective advantages for survival. Under modern environmental conditions, a genetic predisposition to both would result in marked insulin resistance and be a major risk for the development of NIDDM. A low relative metabolic rate and a high insulin sensitivity have been shown to predict weight gain. However, upon the weight gain these "metabolic risks" appear to normalise thus raising doubts about whether these factors are truly aetiological. The thrifty genotype hypothesis remains a valid construct to explain the presence of common, genetically-determined factors which are currently detrimental to health, however, the original mechanisms proposed by Neel of an "efficient" metabolism or hyperinsulinaemia need considerable rethinking in light of 30 years of evidence.