Analysis of time- dependent adaptations in whole-body energy balance in obesity induced by high-fat diet in rats

Background: High-fat (HF) diet has been extensively used as a model to study metabolic disorders of human obesity in rodents. However, the adaptive whole-body metabolic responses that drive the development of obesity with chronically feeding a HF diet are not fully understood. Therefore, this study investigated the physiological mechanisms by which whole-body energy balance and substrate partitioning are adjusted in the course of HF diet-induced obesity. Methods: Male Wistar rats were fed ad libitum either a standard or a HF diet for 8 weeks. Food intake (FI) and body weight were monitored daily, while oxygen consumption, respiratory exchange ratio, physical activity, and energy expenditure (EE) were assessed weekly. At week 8, fat mass and lean body mass (LBM), fatty acid oxidation and uncoupling protein-1 (UCP-1) content in brown adipose tissue (BAT), as well as acetyl-CoA carboxylase (ACC) content in liver and epidydimal fat were measured. Results: Within 1 week of ad libitum HF diet, rats were able to spontaneously reduce FI to precisely match energy intake of control rats, indicating that alterations in dietary energy density were rapidly detected and FI was self-regulated accordingly. Oxygen consumption was higher in HF than controls throughout the study as whole-body fat oxidation also progressively increased. In HF rats, EE initially increased, but then reduced as dark cycle ambulatory activity reached values similar to 38% lower than controls. No differences in LBM were detected; however, epidydimal, inguinal, and retroperitoneal fat pads were 1.85-, 1.89-, and 2.54-fold larger in HF-fed than control rats, respectively. Plasma leptin was higher in HF rats than controls throughout the study, indicating the induction of leptin resistance by HF diet. At week 8, UCP-1 content and palmitate oxidation in BAT were 3.1- and 1.5-fold higher in HF rats than controls, respectively, while ACC content in liver and epididymal fat was markedly reduced. Conclusion: The thermogenic response induced by the HF diet was offset by increased energy efficiency and time-dependent reduction in physical activity, favoring fat accumulation. These adaptations were mainly driven by the nutrient composition of the diet, since control and HF animals spontaneously elicited isoenergetic intake.