Impaired Metabolic Flexibility to High-Fat Overfeeding Predicts Future Weight Gain in Healthy Adults

Abstract

The ability to switch fuels for oxidation in response to changes in macronutrient composition of diet (metabolic flexibility) may be informative of individuals’ susceptibility to weight gain. Seventy-nine healthy, weight-stable participants underwent 24-h assessments of energy expenditure and respiratory quotient (RQ) in a whole-room calorimeter during energy balance (EBL) (50% carbohydrate, 30% fat) and then during 24-h fasting and three 200% overfeeding diets in a crossover design. Metabolic flexibility was defined as the change in 24-h RQ from EBL during fasting and standard overfeeding (STOF) (50% carbohydrate, 30% fat), high-fat overfeeding (HFOF) (60% fat, 20% carbohydrate), and high-carbohydrate overfeeding (HCOF) (75% carbohydrate, 5% fat) diets. Free-living weight change was assessed after 6 and 12 months. Compared with EBL, RQ decreased on average by 9% during fasting and by 4% during HFOF but increased by 4% during STOF and by 8% during HCOF. A smaller decrease in RQ, reflecting a smaller increase in lipid oxidation rate, during HFOF but not during the other diets predicted greater weight gain at both 6 and 12 months. An impaired metabolic flexibility to acute HFOF can identify individuals prone to weight gain, indicating that an individual’s capacity to oxidize dietary fat is a metabolic determinant of weight change.

Adipocyte REVERBα dictates adipose tissue expansion during obesity

“…The reduced inflammation seen in obese Reverbα Flox2-6 Adipo Cre mice is likely multifactorial, but may be secondary to a reduction in the pro-inflammatory free fatty acid pool, resulting from de-repression of lipogenic and mitochondrial metabolism pathways, or the absence of signals from dead/dying adipocytes. It is of note that improved metabolic flexibility is proposed to be beneficial in other mouse models of metabolic disease (Jonker et al, 2012; Kim et al, 2007; Virtue et al, 2018) and in human obesity (Aucouturier et al, 2011; Begaye et al, 2020). We identify extracellular matrix as a new direct target of adipose REVERBα action; altered regulation of WAT collagen production and modification is also likely to contribute to the rapid and continued adipose tissue expansion and reduced obesity-related fibrosis.…”

Pathophysiological role of metabolic flexibility on metabolic health

“…This ability to alternate energy fuels depending on fuel availability (i.e., MetF) assures a constant and sufficient energy supply to organs and cells. At whole‐body level, MetF also appears to influence energy intake and energy balance, 25–27 because impaired MetF associates with an increased risk of weight gain 28–30 …”

Heat Stress Reduces Metabolic Rate While Increasing Respiratory Exchange Ratio in Growing Pigs

“…Diet-induced obesity (DIO)/diabetes and HS share many parallels in their mechanistic disruption of substrate metabolism. Both DIO/diabetes and HS persist with impaired lipid metabolism, decreased metabolic flexibility, increased reliance on carbohydrates as a fuel source, and ultimately increased adiposity [ 2 , 14 , 37 ].…”