Metabolic dysfunction following weight regain compared to initial weight gain in a high-fat diet-induced obese mouse model

Diet-induced weight loss and regain leads to physiological and metabolic changes, some of which are potentially harmful. However, the specific metabolic processes and dysfunctions associated with weight regain, and how they differ from initial weight gain, remain unclear. Thus, we examined the metabolic profiles of mice following weight regain compared to initial weight gain. Mice were fed a normal diet or a high-fat diet or were cycled between the two diets to alternate between obese and lean states. Liver samples were collected and hepatic metabolites were profiled using nuclear magnetic resonance (NMR). The identified metabolites associated with weight regain were quantified using gas chromatography/mass spectrometry (GC/MS) and lipid profiles were assessed using ultra-high-performance liquid chromatography-quadrupole time-of-flight MS (UPLC-QTOF-MS). In addition, changes in expression of pro-inflammatory cytokines and gluconeogenic enzymes were investigated using polymerase chain reaction (PCR) and western blotting, respectively. Hepatic levels of several amino acids were reduced in mice during weight regain compared with initial weight gain. In addition, gluconeogenic enzyme levels were increased following weight regain, indicating an up-regulation of gluconeogenesis. Lipidomic profiling revealed that levels of ceramide and sphingomyelin, which are related to obesity-induced inflammation, were significantly increased during weight regain compared to initial weight gain. Moreover, tumor necrosis factor-α (TNF-α) and transforming growth factor-β1 (TGF-β1) levels were significantly up-regulated during weight regain. In this study, weight regains lead to an up-regulation of gluconeogenesis and aggravated inflammation. Additionally, weight regain can worsen the metabolic dysfunction associated with obesity.