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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 long-lasting enigma of energy balance regulation and facilitate a much-needed breakthrough in the pharmacological treatment of obesity., Competing Interests: The authors have declared that no competing interests exist.

Overfeeding triggers homeostatic compensatory mechanisms that counteract weight gain. Here, we show that both lean and diet-induced obese (DIO) male mice exhibit a potent and prolonged inhibition of voluntary food intake following overfeeding-induced weight gain. We reveal that FGF21 is dispensable for this defense against weight gain. Targeted proteomics unveiled novel circulating factors linked to overfeeding, including the protease legumain (LGMN). Administration of recombinant LGMN lowers body weight and food intake in DIO mice. The protection against weight gain is also associated with reduced vascularization in the hypothalamus and sustained reductions in the expression of the orexigenic neuropeptide genes, Npy and Agrp, suggesting a role for hypothalamic signaling in this homeostatic recovery from overfeeding. Overfeeding of melanocortin 4 receptor (MC4R) KO mice shows that these mice can suppress voluntary food intake and counteract the enforced weight gain, although their rate of weight recovery is impaired. Collectively, these findings demonstrate that the defense against overfeeding-induced weight gain remains intact in obesity and involves mechanisms independent of both FGF21 and MC4R. Overfeeding triggers a mechanistically ill-defined compensatory response that counteracts weight gain. Here, the authors show that the defence against overfeeding is preserved in obesity, and that it is independent from FGF21 and MC4R. [ABSTRACT FROM AUTHOR]

Body weight is under physiological regulation. When body fat mass decreases, a series of responses are triggered to promote weight regain by increasing food intake and decreasing energy expenditure. Analogous, in response to experimental overfeeding, excessive weight gain is counteracted by a reduction in food intake and possibly by an increase in energy expenditure. While low blood leptin and other hormones defend against weight loss, the signals that oppose overfeeding-induced fat mass expansion are still unknown. In this article, we discuss insights gained from overfeeding interventions in humans and intragastric overfeeding studies in rodents. We summarize the knowledge on the relative contributions of energy intake, energy expenditure and energy excretion to the physiological defence against overfeeding-induced weight gain. Furthermore, we explore literature supporting the existence of unidentified endocrine and non-endocrine pathways that defend against weight gain. Finally, we discuss the physiological drivers of constitutional thinness and suggest that overfeeding of individuals with constitutional thinness represents a gateway to understand the physiology of weight gain resistance in humans. Experimental overfeeding, combined with modern multi-omics techniques, has the potential to unveil the long-sought signalling pathways that protect against weight gain. Discovering these mechanisms could give rise to new treatments for obesity. This article is part of a discussion meeting issue 'Causes of obesity: theories, conjectures and evidence (Part I)'. [ABSTRACT FROM AUTHOR]

The obesogenic environment is a key factor in the obesity epidemic that affects many, but not all, humans across the world. Then, body weight, body composition, energy intake, physical activity and energy expenditure were measured during a 10-day baseline period and again during the overfeeding session. [Extracted from the article]

Body weight is defended by strong homeostatic forces. Several of the key biological mechanisms that counteract weight loss have been unraveled over the last decades. In contrast, the mechanisms that protect body weight and fat mass from becoming too high remain largely unknown. Understanding this aspect of energy balance regulation holds great promise for curbing the obesity epidemic. Decoding the physiological and molecular pathways that defend against weight gain can be achieved by an intervention referred to as 'experimental overfeeding'. In this review, we define experimental overfeeding and summarize the studies that have been conducted on animals. This field of research shows that experimental overfeeding induces a potent and prolonged hypophagic response that seems to be conserved across species and mediated by unidentified endocrine factors. In addition, the literature shows that experimental overfeeding can be used to model the development of non-alcoholic steatohepatitis and that forced intragastric infusion of surplus calories lowers survival from infections. Finally, we highlight studies indicating that experimental overfeeding can be employed to study the transgenerational effects of a positive energy balance and how dietary composition and macronutrient content might impact energy homeostasis and obesity development in animals. Experimental overfeeding of animals is a powerful yet underappreciated method to investigate the defense mechanisms against weight gain. This intervention also represents an alternative approach for studying the pathophysiology of metabolic liver diseases and the links between energy balance and infection biology. Future research in this field could help uncover why humans respond differently to an obesogenic environment and reveal novel pathways with therapeutic potential against obesity and cardiometabolic disorders. • Experimental overfeeding in animals involves intragastric delivery of an energy-dense (liquid) diet. • Experimental overfeeding rapidly increases body weight while suppressing voluntary food intake. • Overfeeding-induced hypophagia continues after overfeeding is stopped, driving body weight back to baseline. • Experimental overfeeding is a promising but underutilized resource for identifying weight gain defense mechanisms. [ABSTRACT FROM AUTHOR]

Metformin is a blood-glucose-lowering medication with physiological effects that extend beyond its anti-diabetic indication. Recently, it was reported that metformin lowers body weight via induction of growth differentiation factor 15 (GDF15), which suppresses food intake by binding to the GDNF family receptor α-like (GFRAL) in the hindbrain. Here, we corroborate that metformin increases circulating GDF15 in mice and humans, but we fail to confirm previous reports that the GDF15-GFRAL pathway is necessary for the weight-lowering effects of metformin. Instead, our studies in wild-type, GDF15 knockout, and GFRAL knockout mice suggest that the GDF15-GFRAL pathway is dispensable for the effects of metformin on energy balance. The data presented here question whether metformin is a sufficiently strong stimulator of GDF15 to drive anorexia and weight loss and emphasize that additional work is needed to untangle the relationship among metformin, GDF15, and energy balance. [Display omitted] • The anti-diabetic drug metformin induces secretion of the cellular stress factor GDF15 • Metformin-induced GDF15 secretion is potentiated by a high-fat diet • Metformin lowers body weight independently of GDF15 and GFRAL in obese mice • Metformin increases plasma GDF15 but is not associated with weight loss in humans Activating the GDF15 receptor, GFRAL, can reduce food intake. Klein et al. demonstrate that the widely prescribed anti-diabetic medication metformin lowers body weight independently of the GDF15-GFRAL pathway in mice. In humans with BMI >25 and prediabetes, metformin increases circulating levels of GFD15, but this increase is not associated with weight loss. [ABSTRACT FROM AUTHOR]