Deciphering the Metabolic Benefits of Dietary Medium Chain Fatty Acids

• Applicant: Maximilian Kleinert, Ph.D.
• Subject Area: Endocrinology, Diabetology, Metabolism ; Nutritional Sciences
• Term: since 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 502372044

Type 2 diabetes mellitus (T2DM) causes global suffering and economic burden. Obesity-induced insulin resistance is a key risk factor for developing T2DM. Current treatment strategies are failing to meaningful curb the ongoing obesity and T2DM pandemics, necessitating the continued exploration of alternative, adjunct and better treatment options. Interestingly, dietary intake of special lipids called medium-chain fatty acids (MCFAs), which are fatty acids consisting of 8-12 carbon atoms, has been shown to increase energy expenditure, to limit food intake, and to improve insulin resistance. We very recently found that intake of a small amount of MCFAs can help prevent insulin resistance in humans overfed with a high-fat diet. Despite these diverse systemic metabolic benefits, the mechanisms for how MCFAs achieve these effects are completely unknown. Understanding the mode-of-action of MCFAs has the potential to uncover new pathways within or among different organs that can be discreetly targeted to elicit distinct, personalized metabolic benefits to prevent metabolic disease like T2DM. I am herein pursuing the novel hypothesis that the metabolic benefits of MCFAs relate to their unique metabolism in the liver. Unlike long-chain fatty acids (LCFAs), which make up most fats in diet and body, MCFAs are directly absorbed into the portal vein after digestion, and undergo obligatory β-oxidation in the liver. I postulate that the rapid hepatic MCFA oxidation triggers the release of hepatokines, such as FGF21 and GDF15, which coordinate the systemic metabolic benefits associated with MCFAs intake. In agreement, we have observed increases in circulating GDF15 and FGF21 in mice following oral administration of an oil rich in MCFAs compared to when we gavaged an oil comprised of LCFAs. This was associated with increases in hepatic Fgf21 and Gdf15 mRNA that was specific to the MCFA treatment. The latter also resulted in increased levels of blood ketone bodies. Long viewed as merely starvation metabolites that provide energy to the brain during fasting, ketone bodies are now also considered important signaling molecules with wide-ranging effects on metabolism. Building on our pilot data, we will perform studies in loss-of-function mouse models to understand the contribution of these different hepatic factors (i.e., FGF21, GDF15, GDF15+FGF15, and ketone bodies) to the health benefits of MCFAs. In addition, we will pursue an explorative approach by investigating global gene changes in different organs after MCFA treatment to uncover novel MCFA-induced targets and factors. Overall, this research proposal has the potential to discover several novel multi-organ mechanisms that can targeted to treat or prevent metabolic diseases like type 2 diabetes and obesity.

• DFG Programme: Research Grants