The Impact of Early Human Migration on Brown Adipose Tissue Evolution and its Relevance to the Modern Obesity Pandemic

Dyan Sellayah

Disclosures

J Endo Soc. 2019;3(2):372-386. 

In This Article

Abstract and Introduction

Abstract

Genetic factors are believed to be primarily responsible for obesity; however, an understanding of how genes for obesity have become so prevalent in modern society has proved elusive. Several theories have attempted to explain the genetic basis for obesity, but none of these appear to factor in the interethnic variation in obesity. Emerging evidence is increasingly pointing to a link between reduced basal metabolism and ineffective brown adipose tissue (BAT) thermogenesis. In fact, BAT presence and function are strongly correlated with metabolic rates and directly influence obesity susceptibility. My colleagues and I recently theorized that ancestral exposure to cold necessitated the evolution of enhanced BAT thermogenesis, which, with today's hypercaloric and sedentary lifestyle, becomes advantageous, because thermogenesis is energetically wasteful, raising basal metabolism and burning excess calories. The opposite may be true for the descendants of heat-adapted populations. This review further reconciles global evolutionary climatic exposures with obesity demographics to understand the genetic basis for the obesity pandemic, and new insights from the most recent studies are provided, including those assessing archaic human admixture. Key genetic variants influencing BAT thermogenesis are outlined that have also been linked with climatic exposure to cold and appear to support the theory that evolutionary factors relevant to climate may have shaped the modern obesity pandemic.

Introduction

Obesity has reached pandemic proportions throughout the western world and its socioeconomic impact is crippling. Obesity is particularly problematic because it is a risk factor for aplethora of metabolic diseases that each increase mortality rates. Although the relatively rapid rise in obesity prevalence over the last several decades has fueled the perception that the disease is predominantly environmental, accumulating research has strengthened the concept that genetic factors are mostly responsible for the current obesity pandemic.[1] This is not a novel idea, however. In 1986, in a study of adopted monozygotic twin pairs reared apart, Stunkard et al.[2] showed there was a high within-pair correlation in body mass index (BMI). Conversely, there was no relationship between BMI of adoptive parents and their adoptee. Several similar observations have been documented in comparable adoptive twin study experiments.[3]

It has long been known that interindividual susceptibility to weight gain and obesity is highly variable, even under carefully controlled conditions. In a landmark paper by Bouchard et al.,[4] pairs of adopted monozygotic twins were asked to overeat by 1000 calories/d in a carefully controlled and supervised inpatient study. The study revealed the single most important predictor of body weight gain by an individual twin was the weight gained by the other twin. In fact, there was a large variation in body weight and adiposity between twin pairs but negligible variation within twin pairs. The authors of this study concluded that heritable factors were more decisive in the promotion of obesity than were environmental factors, because twins were raised in separate environments. Energy intake and physical activity were carefully controlled for in this study; therefore, genetic factors involved in basal metabolic rate appear to be the primary determinant of obesity susceptibility in response to overfeeding.

There are three major components of daily energy expenditure: obligatory energy expenditure, which represents the energy required for upkeep of basic biochemical processes at the cellular level within the body; physical activity energy expenditure, which is the energy spent during exercise; and adaptive thermogenesis, which is the production of heat in response to environmental or dietary factors.[5,6] Differences in adaptive thermogenesis, which raises energy expenditure beyond the obligatory energetic threshold, are potentially responsible for the interindividual variation in total daily energy expenditure and, thus, obesity susceptibility.[7] Adaptive thermogenesis involves the uncoupling of ATP synthesis from the electrochemical gradient driven by the electron transport chain. This occurs in the mitochondria of a specialist organ known as brown adipose tissue (BAT). BAT is functionally distinct from white adipose tissue, which predominates in obesity and is primarily concerned with energy storage. The energy wastage mechanism in BAT, which liberates energy in the form of heat, is mediated by uncoupling protein 1 (UCP1). The importance of BAT thermogenesis to maintenance of body temperature in small mammals was well known; however, its presence in adult humans has only recently been established.[8] Although BAT depots have been documented in newborns and shown to play a protective role in response to the negative temperature gradient between the in utero and neonatal environment, it was thought to deteriorate to undetectable levels by adolescence.[9–11] It was not until papers published in 2009 revealed the presence of functionally active BAT in adult humans that BAT's potential therapeutic value in the light of the obesity pandemic was revisited.[12–14]

Studies have estimated that maximally stimulated BAT can contribute as much as 20% to total daily energy expenditure and thus provide substantial resistance in the fight against obesity.[15] Another emerging concept in the field of adipose tissue research is the notion that distinct adipocytes (namely, beige or brite cells) within white adipose depots may undergo conversion to brown adipocytes under certain stimuli, such as cold exposure or sympathetic nerve stimulation.[16] This process of conversion of beige adipocytes to brown adipocytes is termed browning and is particularly therapeutically attractive in light of recent studies that suggest that under thermoneutral conditions, human BAT may be more representative of beige rather than classical BAT depots.[17]

A caveat to the potential therapeutic capabilities of BAT or browning in combating obesity, however, is that BAT maybe absent or reduced in certain ethnic groups. It remains to be determined whether recruitment of BAT or browning mechanisms is equally limited in these ethnic groups, and additional research is required to answer this important question. The question of why various populations have reduced BAT functionality compared with others is an intriguing one, and answers to this immensely important mystery may be found in the evolutionary history of the ancestors of modern humans.

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