The physiology of experimental overfeeding in animals

Abstract

Background: 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'.

Scope of the review: 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.

Major conclusions: 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.

Keywords: Animal models; Body weight; Energy balance; Experimental overfeeding; Intragastric overfeeding; Leptin; NASH; Obesity.

Figure 1

Examples of seasonal overfeeding in nature. The bar-tailed Gotwit and the fat-tailed dwarf lemur are illustrative examples of seasonal overfeeding in nature. The bar-tailed Gotwit migrates between Alaska and New Zealand. The fat-tailed dwarf lemur is a primate hibernator that lives in Madagascar. The graph on the right shows a schematic of circannual cycles of changes in body mass (red line) and food intake (gray line) during the preparatory hyperphagic period and the subsequent migration/hibernation period in bar-tailed Gotwits and fat-tailed dwarf lemurs.

Figure 2

Comparative changes in body weight during and after experimental overfeeding in humans and animals. Typical body weight trajectories reported from experimental overfeeding in humans (A) and experimental overfeeding in animals (B). Experimental overfeeding comprises three distinct phases: 1) Baseline, in which the caloric requirements for weight stability are estimated or measured; 2) experimental overfeeding that can vary in magnitude and duration depending on study objectives; and 3) ad libitum feeding, which typically is reflected by body weight recovery (loss of weight gained during overfeeding). The dotted red lines in phase 3 in (A) reflect the substantial inter-individual variation in post-overfeeding body weight recovery in humans.

Figure 3

Experimental overfeeding studies in small rodents have not increased over time. The yearly number of retrieved papers from Pubmed on experimental overfeeding in small rodents is shown in red bars. For comparison, the yearly number of retrieved papers from Pubmed on diet-induced obesity in small rodents is shown in gray bars.

Figure 4

Food intake, body weight, and hormonal changes during and after experimental overfeeding in rodents. (A) Schematic graphs showing changes in energy intake and body weight during and after experimental overfeeding. Energy intake is divided into total energy intake (red) and voluntary energy intake (gray), highlighting the suppression of voluntary food intake during overfeeding and the prolonged period of voluntary hypophagia after the cessation of overfeeding coinciding with return of body weight to baseline. (B) Schematic graphs showing reported changes during and after experimental overfeeding (representation from different studies) in three hormones important for energy homeostasis: leptin, insulin, and ghrelin. The data highlight that the hormones change substantially during overfeeding, but also that they return to baseline plasma levels before food intake has normalized – indicating that they are dispensable for the prolonged hypophagia following overfeeding.

Figure 5

Potential tissue sources and effects on energy balance of circulating factors of overfeeding. Schematic diagram showing the hypothesized potential tissue sources of circulating factors of overfeeding. The potential sources represented in this figure are weight-bearing bones, skeletal muscle, white adipose tissue, gastrointestinal tract, liver and pancreas. Potent factors of overfeeding are predicted to exert regulation of energy balance via central nervous system mechanisms implicating inhibition of food intake and possibly also stimulation of energy expenditure and/or calorie excretion.

Figure 6

Effect of experimental overfeeding on infection survival. Examples from literature in which the role of energy surplus in the form of experimental overfeeding has been evaluated for infection survival in animals.

Figure 7

Features and utility of experimental overfeeding in animals. Schematic overview of the major physiological underpinnings and suggested utility of experimental overfeeding in animals.