Gottmann, P. | bioRxiv Science

bioRxiv2025

Nutritional hyperketonemia by dietary medium-chain fatty acids is driven by the liver without contribution from the intestine

Saturated medium-chain fatty acids (MCFAs) are ketogenic nutrients, and their dietary intake has been linked to health benefits such as improved energy balance and increased insulin sensitivity. Here, we tested the hypothesis that MCFA-mediated hyperketonemia is required for these benefits. Using tissue-specific 3-hydroxy-3-methylglutaryl-CoA synthase 2 (Hmgcs2) knockout mouse models, we show that the hyperketonemia induced by oral administration of triacylglycerols with the MCFA octanoic acid (C8:0-MCT) is mediated by hepatic, but not intestinal, ketogenesis. Remarkably, acute reductions in food intake and body weight induced by C8:0-MCT in obese mice were independent of hepatic ketogenesis; likewise, chronic protection against weight gain and marked improvements in insulin sensitivity elicited by MCFA-rich diets did not require hepatic ketogenesis. These data demonstrate that dietary MCFAs are potent bioactive lipids capable of inducing metabolic benefits independently of their ketogenic properties.

physiology↗

bioRxiv2023

Pantothenate Kinase 4 controls efficient skeletal muscle energy substrate metabolism via acetyl-CoA

Metabolic inflexibility in skeletal muscle (SkM) is closely linked to metabolic diseases. Exercise improves metabolic flexibility, rendering it a valuable discovery tool of mechanisms promoting efficient metabolism of glucose and lipids. We herein discover pantothenate kinase 4 (PanK4) as a conserved exercise target with high abundance in SkM. We go on to show that murine muscle Pank4 is dysregulated with high-fat diet feeding, and identify human PANK4 variants that associate with glycemic control and body mass index traits, indicating important roles of PanK4 in glucose metabolism and growth. Consistent with the latter, germline deletion of PanK4 reduces circulating IGF-1 and stunts growth in mice. Deletion specifically in mouse SkM reveals that PanK4 facilitates fatty acid oxidation by acting as a regulator of SkM acetyl-CoA, a key node in metabolism of both glucose and lipids. Consequently, without PanK4, elevated SkM acetyl-CoA levels allosterically gridlock key enzymes required for efficient lipid and glucose utilization, and these SkM metabolic perturbations manifest in whole-body insulin resistance. As proof of principle, we show that an increase in muscle PanK4 lowers SkM acetyl-CoA and increases SkM glucose utilization. Our findings identify PanK4 as a novel regulator of SkM energy substrate metabolism, warranting inclusion in comprehensive strategies against metabolic disease.

physiology↗