The unidentified hormonal defense against weight gain

Abstract

Human biology has evolved to keep body fat within a range that supports survival. During the last 25 years, obesity biologists have uncovered key aspects of physiology that prevent fat mass from becoming too low. In contrast, the mechanisms that counteract excessive adipose expansion are largely unknown. Evidence dating back to the 1950s suggests the existence of a blood-borne molecule that defends against weight gain. In this article, we discuss the research supporting an "unidentified factor of overfeeding" and models that explain its role in body weight control. If it exists, revealing the identity of this factor could end a longlasting enigma of energy balance regulation and facilitate a much-needed breakthrough in the pharmacological treatment of obesity. Obesity and its biological roots Historically, fatness was a desirable attribute associated with social status, wealth, and fertility [1,2]. Although this view is still dominant in certain cultures, the Western world recognizes adiposity as a chronic condition that hampers human health [3]. Individuals with obesity are often stigmatized [4], and many lean individuals erroneously believe that severe overweight is a self-inflicted situation caused by eating too much and exercising too little. The simplicity of this thinking is opposed by the complex causes of obesity [5] and by the "brainteasing" biology that makes it very hard for millions of people to fight their own fat mass [3]. Biomedical assistance is likely needed to win this battle, and in order to provide this support, perhaps it is time for obesity scientists to consider the less-beaten research paths. Instead of searching for yet another slimming agent, it might be better to reveal why some people easily put on pounds while others stay lean. In contrast to conventional assumptions about superior self-control and willpower, human studies have demonstrated that weight gain resistance has deep biological roots [6,7] (Fig 1). Characterizing these is among the critical steps toward an improved understanding of obesity etiology. Importantly, geneticists have finally started to uncover the genome of thinness [8,9], but their efforts might be fruitless unless physiologists determine the fundamental features of fat mass regulation encoded by these genes.

Dietary intervention improves health metrics and life expectancy of the genetically obese DU6 (Titan) mouse

“…At 16-17 weeks of age, Titan mice showed multifocal fatty cells in the pancreas, usually termed pancreatic lipomatosis or steatosis, without atrophic or inflammatory changes of the adjacent parenchyma, a phenotype not present in control mice (Figure 2G). We also found that the average levels of leptin, a hormone secreted by adipocytes( 3 , 5 , 19 ) and known to modulate food intake and fat storage ( 3 , 5 , 19 ), were significantly higher (more than 5-fold; P < 0.001) in 16-17-week-old Titan mice compared to control mice (Figure 2H). Finally, we investigated whether the plasma concentration of fibroblast growth factor 21 (FGF21), a factor associated with MetS in humans ( 20 , 21 ), was altered in Titan mice.…”

“…Consistent with the notion that hyperlipidemia usually occurs in the presence of insulin resistance, insulin levels were more than 3-fold higher in ad libitum 16-17-week-old Titan mice (Figure S1D). We also measured average levels of leptin, a hormone secreted by adipocytes and known to modulate food intake and fat storage [16][17][18] . Leptin levels were significantly higher (more than 5-fold; P < 0.001) in 16-17-week-old Titan mice compared to control mice (Figure S1E).…”

“…In this work, we set out to test the hypothesis that the obese Titan mice developed typical hallmarks of pathological detrimental obesity (MUO) 14 . To address this hypothesis, we conducted a deep phenotypic characterization of the mice and investigated factors involved in detrimental obesity in humans or other model species such as plasma levels of cholesterol and triglycerids 16 , Leptin [16][17][18] , FGF21 19,20 , heart morphology 21 and whitening of adipose tissue 22 .…”

Physiology of weight regain: Lessons from the classic Minnesota Starvation Experiment on human body composition regulation

“…122,123 This contention is further emphasized by evidence that protection against weight gain involves unidentified blood-borne factors. 124,125 A nonleptin system (and so far unidentified adipostatic signals) has recently been implicated in the compensatory hypophagia that plays a critical role in the recovery from rapid weight gain induced by overfeeding. 126 On the other hand, the notion of a feedback loop between FFM deficit and compensatory hyperphagia (Figure 9), as suggested by the MSE reanalysis 63 and by recent studies of weight regain after caloric restriction in humans [98][99][100][101][102] and in mice, 127…”

“…Furthermore, circulating leptin alone does not explain all the findings of parabiotic experiments that have been crucial in the demonstrations that circulating factors are involved in the long‐term control of food intake and weight regulation 122,123 . This contention is further emphasized by evidence that protection against weight gain involves unidentified blood‐borne factors 124,125 . A nonleptin system (and so far unidentified adipostatic signals) has recently been implicated in the compensatory hypophagia that plays a critical role in the recovery from rapid weight gain induced by overfeeding 126 .…”