Adverse metabolic effects of a hypercaloric, high-fat diet in rodents precede observable changes in body weight

Although a high-fat diet (HFD) is recognized as an important contributor to obesity, human research is limited by confounders such as income, whereas animal research has typically examined diet during specific developmental periods rather than throughout the lifespan. We hypothesized that the use of an HFD in short-term studies as has been commonly done in animals does not adequately reflect the lifelong dietary patterns seen frequently in humans with consequent metabolic disturbances. We examined the impact of HFD from weaning until 39 weeks (middle age) on the metabolism of male rats. At 7, 26, and 39 weeks, glucose tolerance tests were performed, a subset of animals was euthanized, and serum and tissues were collected. After 4 weeks, preceding increased body weight, HFD animals had increased intra-abdominal fat, triglycerides, and hyperglycemia. Hyperinsulinemia was insufficient to maintain normoglycemia, and beta cell mass and glucagon-like peptide 1 decreased over time in HFD and control animals. Despite lacking significant lipid abnormalities, nonalcoholic fatty liver disease was evident by 39 weeks. Our HFD model demonstrated that significant metabolic abnormalities may go undetected by current standard screening such as weighing and biochemistry.