Gut Microbiota Restores Central Neuropeptide Deficits Present in Germ Free Animals

Recent work has shown that gut microbiota plays an important role in host energy homeostasis. Indeed, germ‐free (GF) mice have lower levels of adiposity and leptin levels compared to conventionalized mice. Additionally, GF mice are resistant to obesity when placed on a high‐fat diet. Studies show that gut microbiota contributes to obesity by increasing energy extraction, promoting inflammation, and altering lipogenic and adipogenic enzymes. Moreover, recent work demonstrates the ability of the microbiota to alter expression and release of gut peptides that control appetite and regulate energy homeostasis. However, little is known about the neuronal response of these hormones in GF animals, especially leptin, which is strikingly decreased in these animals. Therefore, we aimed to determine the sensitivity of leptin in GF mice compared to conventional mice by injecting leptin and measuring levels of leptin receptor activation via STAT3 and PI3K pathways in the hypothalamus and hindbrain. We also measured expression of orexigenic and anorexigenic peptides in the hypothalamus and hindbrain to examine whether gut microbiota impacts central nervous system regulation of energy homeostasis. We found that GF mice had a significant increase in hypothyalamic NPY and AgRP mRNA expression and a decrease in hindbrain NPY and AgRP mRNA. mRNA expression of POMC and CART remained unchanged. Protein expression of hypothalamic STAT3 and pERK/ERK increased significantly in response to peripheral leptin. Further, administration of leptin normalized circulating levels of leptin, GLP‐1, PYY and ghrelin, all of which were significantly decreased in GF mice. Conventionalization of GF mice (10 days) restored the deficits in hypothalamic and hindbrain neuropeptides present in GF animals. These results show that gut microbiota regulates hypothalamic and hindbrain orexigenic/anorexigenic neuropeptide expression. This is in line with the role of gut microbiota in lipid metabolism and fat deposition that may contribute to excess fat in conventionalized animals under high feeding condition. Support or Funding Information Romanian National Program PN‐II‐ID‐PCE‐2012‐4‐0608 no. 48/02.09.2013, “Analysis of novel risk factors influencing control of food intake and regulation of body weight”