Obesity—A Disease With Many Aetiologies Disguised in the Same Oversized Phenotype

Has the Overeating Theory Failed?

Peter Stenvinkel


Nephrol Dial Transplant. 2015;30(10):1656-1664. 

In This Article

Thrifty Gene Hypothesis—Did Double 'Knock-outs' Predispose to Obesity?

In 1962, the thrifty gene hypothesis was proposed by James Neel[50] to explain why insulin resistance and obesity have increased so much when food is abundant. The theory postulates that acquisition of genes during periods of famine predisposes to an obese phenotype. As no acquisition of thrifty genes has yet been identified, it has been speculated that gene knockouts may instead have functioned as the 'thrifty phenotype'.[51] Johnson et al.[51] propose that mutations in both the uricase (resulting in higher uric acid levels) and l-gulono-gamma-lactone (resulting in an inability to synthesize vitamin C) genes have predisposed to fat mass accumulation during food-abundant periods. In animals, fructose-induced elevation of uric acid and subsequent insulin resistance and fat mass accumulation may have provided an essential adaption to survive periods of starvation and/or to prepare for long periods of fasting during hibernation or migration.[26] In a comparative study of hibernating and summer active brown bears, we observed a positive correlation between changes in fructose and uric acid.[28] Thus, high uric acid levels in the active summer period may depend on increased fructose intake.