Impact of Short-Term Lipid Overload on Whole-Body Physiology

Abstract

Complex metabolic diseases due to overnutrition such as obesity, type 2 diabetes, and fatty liver disease are a major burden on the healthcare system worldwide. Current research primarily focuses on disease endpoints and trying to understand underlying mechanisms at relatively late stages of the diseases, when irreversible damage is already done. However, complex interactions between physiological systems during disease development create a problem regarding how to build cause-and-effect relationships. Therefore, it is essential to understand the early pathophysiological effects of overnutrition, which can help us understand the origin of the disease and to design better treatment strategies. Here, we focus on early metabolic events in response to high-fat diets (HFD) in rodents. Interestingly, insulin resistance, fatty liver, and obesity-promoting systemic inflammatory responses are evident within a week when mice are given consecutive HFD meals. However, as shown in human studies, these effects are usually not visible after a single meal. Overall, these results suggest that sustained HFD-intake within days can create a hyperlipidemic environment, globally remodeling metabolism in all affected organs and resembling some of the important disease features.

Keywords: MASLD; NEFA; Short-term high-fat diet (HFD); insulin resistance; lipid infusion; metabolism; spill-over; type 2 diabetes (T2D); whole-body physiology.