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

Insulin Resistance—An Adaptive Trait Not Always Linked to Obesity

Insulin resistance with hyperinsulinaemia is recognized as the common denominator linking a hypercaloric intake with fat accumulation. Insulin resistance is highly prevalent in CKD and is primarily related to increased fat mass.[19] Although insulin resistance is believed to be involved in the pathogenesis and cardiometabolic complications of CKD, insulin sensitivity scores did not predict mortality in patients with impaired renal function.[20] Some evidence argue against the current view of insulin resistance as an obligatory injurious response to fat accumulation.[5] At first, obesity and insulin resistance do not always coexist. In fact, 20–30% of obese subjects are metabolically normal[21] and characterized by enhanced capacity for storing fat in adipose tissue, lower visceral adiposity, higher adiponectin, less inflammation and lower macrophage infiltration in adipose tissue.[22] This 'favourable fat phenotype' is not associated with coronary heart disease and type 2 diabetes.[23] On the other hand, some patients with normal weight manifest components of insulin resistance and its complications, such as type 2 diabetes, dyslipidaemia, NAFLD and CVD.[24] Insulin resistance and obesity are also disjointed in animal models, such as in the extremely lean caveolin knockout mice, with massive metabolic dysfunction.[25] Thus, features of metabolic syndrome and insulin resistance can occur independently of weight gain.

Diet-induced insulin resistance and fat accumulation are fundamental for survival in many animal species to prepare for periods of food shortage and hibernation.[26] As insulin resistance could represent a normal physiological process for survival during starvation periods, metabolic syndrome could be regarded as normal fat storage condition.[26] Although bears (Ursidae) develop massive obesity, dyslipidaemia, insulin resistance and even type 2 diabetes in preparation for winter hibernation, muscle loss, inflammation, oxidative stress and atherosclerotic lesions does not ensue.[27–29] Intriguing recent data based on studies of Grizzly bears show that these 'metabolic magicians' have augmented insulin sensitivity while obese and that insulin resistance function as gatekeeper in the transition from feeding to fasting during hibernation.[30] Based on studies on bears and other hibernating animals, such as marmot and squirrel, activation of processes that lead to hyperphagia, reduced metabolism and overweight prior to hibernation is fundamental for survival. Thus, we should reappraise the metabolic syndrome and consider insulin resistance as an adaptive evolutionary conserved response to excess nutrient intake.[26] Clearly, this metabolic trait was beneficial also in man until we were exposed to the modern obesogenic milieu. In certain clinical conditions, such as in pregnancy and during infections, insulin resistance has developed as a protective mechanism to ensure that glucose is reserved for the priority cells.[5] Taken together, the common uncoupling between insulin resistance and obesity, and the protective effects of insulin resistance in certain clinical conditions, indicates that the causality between excess food intake, obesity and its related disorders is not as strong as believed.