Nutrients, Intestinal Microbiota and Obesity
Contact: Dr. Karolin Weitkunat
Funding: Deutsche Forschungsgemeinschaft (DFG)
Macronutrients are central for energy homeostasis and as such directly implicated in the development of obesity and metabolic disorders. In this regard, also the intestinal microbiota is of importance, especially with regard to the production of short chain fatty acids (SCFA) from fibers.
Fermentable fibers such as guar and inulin affect the composition of intestinal microbiota differently. Interestingly, in mouse feeding studies inulin but not guar showed beneficial metabolic effects which were associated with an increased production of SCFA, mainly propionate. Similar to dietary supplementation of propionate, supplementation of inulin prevented the development of diet induced obesity, fatty liver, and insulin resistance. (Weitkunat et al., 2015; Weitkunat et al., 2016; Weitkunat et al., 2017). Interestingly, in all these studies the beneficial metabolic effects were tightly associated with increased liver and plasma concentrations of odd chain fatty acids (OCFA: C15:0 und C17:0) (Fig. 1.1.).
This supports evidence from human nutritional studies on the importance of OCFA for human health. Possibly, OCFA play a protective role in various diseases such as multiple sclerosis, Alzheimer and cardiovascular disease. Increased blood concentrations of OCFA are also associated with an improved insulin sensitivity and reduced type 2 diabetes risk. However, these studies show correlations only while causal relationships and underlying biological mechanisms are still uncertain. Our aim is thus to delineated the causal and mechanistic relations between nutrients, SCFA, OCFA and metabolic function.
Using human hepatocytes and a short-term intervention study we could already demonstrate an endogenous synthesis of OCFA from propionate with C17:0 as the end product (Weitkunat et al., 2017). From epidemiological studies it is known that increased plasma C17:0 levels are associated with an increased insulin sensitivity. This fits to our mouse studies which showed that an increased propionate availability can prevent obesity, insulin resistance and fatty liver. This applies to endogenously produced propionate from fiber as well as dietary supplementation of propionate itself. In the liver propionate is transformed into propionyl-CoA (Pr-CoA) which competes with acetyl-CoA as a substrate for fatty acid synthesis, thus resulting in an increased synthesis of OCFA. We are hypothesizing that the increased availability of Pr-CoA is responsible for the beneficial metabolic effects with increased OCFA serving as a biomarker. Currently we investigate the possible contribution of other nutrients such as specific amino acids to increased hepatic levels of OCFA and Pr-CoA, respectively (Fig. 1.2.). We are also investigating possible mechanisms for a causal connection between increased OCFA and a reduced risk for metabolic complications. To this end we are performing feeding studies with mice in vivo as well as investigations on primary hepatocytes in cell culture in vitro.