Gut microbial metabolite delta - valerobetaine (VB) influences energy metabolism by altering fat utilization and satiety-related hormones in mice

There is mounting evidence that the gut microbiota exerts profound influences on systemic homeostasis and metabolism, including effects on host energy metabolism, fatty acid oxidation, and obesity. However, we know little about how the microbiota mechanistically influences these aspects of host biology. Previously, we used mass spectrometry-based metabolomics platforms to demonstrate remarkable differences in the metabolite composition in the hepatic mitochondria of germ-free (GF) and conventional mice and identified Δ-valerobetaine (VB) as a key discriminative molecule. VB was undetectable in GF mice but present in conventional mice. We showed that VB is produced by specific bacterial species and inhibited mitochondrial fatty acid oxidation by suppression of the carnitine shuttle. VB administration to GF and conventional mice increased visceral fat mass and exacerbated hepatic steatosis with a Western-style diet but not a chow control diet and can thus function as a microbiota-derived obesogen. Here we show that VB impacts the physiological aspects of energy metabolism. VB reduces the Oxygen consumption rate (OCR) in HEPG2 cells and alters mitochondria-related protein markers (PGC1α, AMPKα, TFAM) suggesting changes in VB can alter the function of mitochondria. To evaluate whole animal consequences, we utilized the CLAMS-HC metabolic cage system to measure the respiratory exchange ratio (RER) in conventional mice. We found that western diet-fed animals treated with VB (IP 50mg/kg) for a week significantly increased RER compared to control groups on the same diet, whereas there was no impact of VB on regular chow diet-fed animals. Higher RER indicates the usage of glucose rather than the usage of fat, thus shifting the resources to produce energy and enhancing the accumulation/retention of adipose tissue. We also found a significant increase in food intake among VB-treated animals regardless of diet. We further investigated the impact of VB on energy-regulating hormones from serum and found a significant alteration in leptin and ghrelin levels. These data suggest VB alters energy utilization in a diet-dependent fashion possibly through regulating energy satiety hormones. Manipulation of VB levels by changing the intake of dietary precursors, or with VB-producing bacterial taxa, may provide therapeutic approaches to disorders of energy/lipid metabolism. This project has been funded by U.S. NIH R01 AI64462. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.