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

Abstract and Introduction


Evolution has led to metabolic thrift in humans—a genetic heritage that, when exposed to the modern 'obesogenic' milieu with energy-dense food and a sedentary lifestyle, predisposes to obesity. The current paradigm that overeating of easily digestible carbohydrates and the resulting imbalance between energy in and out as the cause of overweight has recently been challenged. Indeed, studies suggest that the host response to various nutrients contributes to overeating and fat accumulation. Alterations in neurotransmitter functions, changes in the epigenome, dysbiosis of gut microbiota and effects of specific nutrients (or lack of such nutrients) on mitochondrial function and signalling pathways may promote fat accumulation independent of calories. Whereas nutrients that stimulate generation of uric acid (such as fructose and purine-rich food) cause insulin resistance and fat accumulation, other nutrients (such as antioxidants, plant food, probiotics, nuts, soy and omega-3) counteract the negative effects of a calorie-rich diet by salutary effects on mitochondrial biogenesis. Thus, the specific metabolic effects of different nutrients may be more important than its total energy content. By studying the impact of nutrients on mitochondrial health, as well as the trans-generational impact of nutrients during fetal life, and how specific bacterial species correlate with fat mass accumulation, new dietary targets for obesity management may emerge. Overeating and overshooting of calories could to a large extent represent a symptom rather than a cause of obesity; therefore, hypocaloric diets should probably not be the main, and certainly not the only, focus for treatment of the obese patient.

Saying that obesity is caused by eating too much is like saying that allergies are caused by breathing too much.—Jonathan Bailor


We experience a global pandemic of obesity and metabolic syndrome. This epidemic has important implications for both cardiovascular disease (CVD) and chronic kidney disease (CKD). As obese patients have a greater incidence of glomerular nephropathies, nephrologists should be well educated about aetiology, assessment and treatment of obesity.[1] Accurate prevention and treatment of obesity in the general population may be one of the most important action points for health officials to prevent the increased worldwide prevalence of CKD.[1] The increasing overweight trend is a worldwide concern and the proportion of adults with a body mass index (BMI) of >25 kg/m2 increased between 1980 and 2013 from 28.8 to 36.9% in men and from 29.8 to 38.0% in women.[2] Disappointingly, no national success stories to combat the obesity epidemic have been reported in the past 33 years.[2] The USA has the highest BMI among high-income countries, and as one in four military service applicants is rejected due to obesity, the surgeon general and the chairman of the US Joint Chiefs of Staff declared obesity a 'threat to US national security'.[3] Like any chronic disease affecting a large part of the population, the pathophysiology of obesity is extremely complex. It includes a complicated combination of genetic predisposition (thrifty genes), behavioural changes and the environment. Metabolic inflammation is an integral part of obesity[4] and serves as a link to insulin resistance.[5] How nutritional imbalance may promote insulin resistance and inflammation is depicted in Figure 1.

Figure 1.

Schematic presentation on how a dysregulated nutrient intake may promote insulin resistance and metabolic inflammation. A chronic dysregulation of nutrition in combination with decreased energy expenditure triggers intrinsic cell dysfunctions that include abnormal protein modification, mitochondrial dysfunction, oxidative and endoplasmic reticulum stress and lipid dysregulation. Cellular dysfunction in turn activates or inhibits a number of regulatory signalling pathways that contribute to impaired insulin signalling, insulin resistance and augmented inflammatory response. A dysregulated nutrient intake may also bypass cellular intrinsic stress responses and contribute to inflammation via stimulation of innate immune receptors, translocation of lipopolysaccharides (LPS) and altered gut microbiota. Figure based on text from Odegaard and Chawla [5].

Diet is likely the most important and modifiable determinant of human health. More energy-dense foods are believed to be a major cause of obesity, type 2 diabetes, non-alcoholic fatty liver disease (NAFLD) and CKD.[6] Although evidence suggests that caloric intake itself may affect risk for CKD, it is difficult to quantify the effects of specific nutritional factors that mediate obesity or CKD.[7] There are compelling reasons to believe that too many calories are not the only (or even the most important) cause of the obesity epidemic. Obesity is considered an energy balance disorder caused by an imbalance between low energy expenditure and increased caloric intake, which results in storage of excess fat. This theory has recently been questioned.[8] Although relationships exist between the prevalence of obesity and the number of McDonald's restaurants[9] as well as physical inactivity,[10] evidence suggests that the overshooting of calories and/or sedentary lifestyle cannot alone explain the overweight epidemic. Instead, a much more complex sum of coexisting alterations, including altered neurotransmitter activity,[11] changes in the epigenome,[12] gut microbiota,[13] adenovirus infection[14] and metabolic changes triggered by specific nutrients,[15,16] may cause overweight.