Preclinical models for obesity research

Abstract

A multi-dimensional strategy to tackle the global obesity epidemic requires an in-depth understanding of the mechanisms that underlie this complex condition. Much of the current mechanistic knowledge has arisen from preclinical research performed mostly, but not exclusively, in laboratory mouse and rat strains. These experimental models mimic certain aspects of the human condition and its root causes, particularly the over-consumption of calories and unbalanced diets. As with human obesity, obesity in rodents is the result of complex gene-environment interactions. Here, we review the traditional monogenic models of obesity, their contemporary optogenetic and chemogenetic successors, and the use of dietary manipulations and meal-feeding regimes to recapitulate the complexity of human obesity. We critically appraise the strengths and weaknesses of these different models to explore the underlying mechanisms, including the neural circuits that drive behaviours such as appetite control. We also discuss the use of these models for testing and screening anti-obesity drugs, beneficial bio-actives, and nutritional strategies, with the goal of ultimately translating these findings for the treatment of human obesity.

Keywords: Binge eating; Epigenetics; Obesity; Transgenics.

Fig. 1.

Brain regions involved in food intake. (A) A sagittal section through a mouse brain showing the relative positions of several regions (nuclei) of importance in aspects of food intake and energy balance: the nucleus of the solitary tract (NTS) and the parabrachial nucleus (PBN) are involved in receiving and relaying signals from the intestinal tract to other regions of the brain; the hypothalamic nuclei – the arcuate nucleus (ARC), ventromedial nucleus (VMN), lateral hypothalamus (LHA) and paraventricular nucleus (PVN) – contribute to the homeostasis of appetite and energy balance; the hippocampus (HIP) is involved in memory and learning associated with food intake; the ventral tegmental area (VTA; midbrain region) and nucleus accumbens (Nuc Acc; striatal region) are associated with registering the rewarding properties of food. (B) A coronal section through the brain in the region of the hypothalamus showing the relative positions of several aforementioned nuclei plus the amygdala (AMY), a region involved in memory and learning, and the ependymal layer surrounding the third ventricle (3V) where tanycytes located in the ventral third of this layer reside (highlighted in red).

Fig. 2.

Computerised food-intake monitoring from a binge-like eating study. This figure illustrates findings based on unpublished data (T. Bake, D. G. A. Morgan and J.G.M.). Rats were given ad libitum access to: chow (CON); a 60% high-fat (HF) diet for 24 h per day (24 h 60%); or continuous access to chow and scheduled access to HF diet for 2 h in the dark phase, as either a single 2 h period (2 h 60%) or as two 1 h periods (2×1 h 60%). (A) Shows weight of food consumed, including from HF diet during scheduled feeding. (B) Shows food intake, excluding that from HF diet during scheduled feeding. These results show that: (1) intake is heavily nocturnal (ZT13-ZT24; zeitgeber time 0 is lights on in a 12:12 h light:dark phase that entrains biological rhythms) under all regimes; (2) rats given scheduled access to HF diet also consume chow during these periods; (3) rats consume a higher proportion of their daily caloric intake as HF diet when given 2×1 h access compared to a single 2 h scheduled feed; (4) compensatory reductions in chow intake were observed in the HF schedule-fed groups during the dark phase prior to and after HF binge-like eating.