Weight gain model in prepubertal rats: prediction and phenotyping of obesity-prone animals at normal body weight

Abstract

Objective: Male Sprague-Dawley rats maintained from birth on a high-fat diet were examined to determine whether a specific measure before puberty can identify and allow one to characterize prepubertal rats at normal weight with high vs low risk for adult obesity. Materials and methods: Measures from weaning (day 21) to around puberty (day 45) were taken of weight gain, absolute body weight and daily energy intake on a high-fat diet and related to the amount of body fat accumulated at maturity (80-100 days of age). Rats identified by a specific prepubertal measure as obesity-prone (OP) vs obesity-resistant (OR) were then characterized before and after puberty. Results: Prepubertal weight gain from days 30 to 35 of age was the strongest and earliest positive correlate of ultimate body fat accrual in adult rats. The highest (8-10 g/day) compared to lowest (5-7 g/day) weight-gain scores identified accurately and reproducibly distinct OP and OR subgroups at day 35 that became obese or remained lean, respectively, as adults. The OP rats with rapid prepubertal weight gain and 50% greater adiposity at maturity (day 100) exhibited the expected phenotype of already-obese rats. These included elevated levels of leptin, insulin, triglycerides and glucose, increased galanin (GAL) peptide levels in the paraventricular nucleus (PVN) and reduced neuropeptide Y (NPY) levels in the arcuate nucleus (ARC). Before puberty (day 35), the OP rats with normal fat pad weights, energy intake and endocrine profile similar to OR rats exhibited these disturbances characteristic of obese rats. They had decreased capacity for fat oxidation in muscle, increased GAL expression in PVN and reduced expression of NPY and agouti-related protein in ARC. Conclusion: Prepubertal weight gain can identify OP rats on day 35 when they have minimal body fat but exhibit specific metabolic and neurochemical disturbances expected to promote obesity and characteristics of already-obese adult rats.

Withdrawal from free-choice high-fat high-sugar diet induces craving only in obesity-prone animals

“…It is notable that there was no correlation between fat or sugar preference and amount of weight gain. A rapid initial weight gain on a high-fat diet is used to predict whether an individual will be obesity-prone (Leibowitz et al 2007) but a similar predictive characteristic pattern of food consumption was not observed in our HFHS diet.…”

“…Obesity-prone (OP) individuals gain weight after diet-induced obesity while obesity-resistant (OR) individuals do not differ in weight from normally fed control individuals (Levin et al 1997;Wang et al 1998). Animals divided in this way have divergent characteristics depending on the paradigm used, and examples of these include a greater preference for fat (Boggiano et al 2007), faster initial weight gain on a high-fat diet (Leibowitz et al 2007), greater insulin and glucose levels (Wang et al 1998) and greater leptin levels (Alexander et al 2006) in OP vs OR individuals. One key disadvantage of the diet-induced obesity method is the lack of choice over food consumption.…”

Factors influencing individual variability in high fat diet-induced weight gain in out-bred MF1 mice

“…Studying this individual variability in responses could reveal processes of individual weight regulation and establish the biological factors that make people either susceptible or resistant to weight gain, which is crucial to increase our understanding of the aetiology of obesity. For example, in male Sprague Dawley rats on pure macronutrient or high fat diets, measures of weight gain, energy intake or fat preference are shown to vary considerably in direct proportion to ultimate body fat gain ( [28,39,49], also see [55] in mice).…”

“…Animal models have been developed that include HFD-induced obesity-prone and -resistant animals (rats [28,30,31,35] and mice [20]) and these animals have been shown to differ in their energy intake, glucose tolerance (GT), expression of (an)orexigenic neuropeptides and responses to CR [4,20,31,37]. These responses are generally observed after obesity has developed, and it is thus unclear whether they are the cause of differences in weight gain between animals fed HFDs, or a consequence of variable responses to the HFD.…”

Expression of Genes for Appetite-Regulating Peptides in the Hypothalamus of Genetically Selected Lean and Fat Sheep

“…Regarding energy sufficiency, there is little difference between normal and excess levels of leptin, in regard to the set-point of appetite-regulating systems in the brain and high levels of leptin in animals of increased adiposity do not provide a feedback signal to reduce food intake [65,66,67]. High levels of adiposity lead to a decrease in NPY mRNA expression in sheep [68] and in diet-induced obese rats [69,70]. In genetically lean and fat mice, NPY mRNA expression in the hypothalamus was not different between groups under normal feeding conditions but was higher in the lean line than in the fat line in a fasted state [71].…”