The regulation of fatty acid mobilization is extravagant rather than frugal: a perspective indicating a limitation of the thrifty genotype hypothesis.

It has been previously proposed that humans are prone to type 2 diabetes because of thrifty genes. It was suggested that the evolution of humans following their split from other primate lineages was uniquely afflicted with cycles of feast and famine, leading to a strong drive to acquire and sequester energy to prepare for future bouts of negative energy balance. In this previous theory, the thrifty genotype hypothesis, it was postulated that this thriftiness led to obesity and type 2 diabetes. The concept of thriftiness may apply to some but not all aspects of metabolism. Here, a major exception to the concept of thriftiness is proposed, noting that in lipid metabolism, there is typically an excess of energy mobilization rather than a conservative or cautious regulation of free fatty acid (FFA) mobilization. On the basis of review and interpretation of literature, it is proposed in this perspective article that a fundamental reason for obesity-related comorbidities is that the body is not sufficiently thrifty in its fat metabolism. Rather than regulation of fatty acid mobilization being frugal, it is instead quite extravagant, with excessive FFA release from adipose tissue being a common occurrence in humans and other animals. Experimental evidence suggests that a rising plasma FFA level worsens insulin resistance, and conversely, making FFA mobilization thriftier (slowing FFA mobilization) improves insulin sensitivity. It is concluded that fatty acid trafficking is inherently unthrifty and that this lavish approach for regulating fat metabolism contributes to the high incidence of pre-diabetes and type 2 diabetes.