title: The gut microbiota reduces leptin sensitivity and the expression of the obesity-suppressing neuropeptides proglucagon (Gcg) and brain-derived neurotrophic factor (Bdnf) in the central nervous system.
abstract: The gut microbiota contributes to fat mass and the susceptibility to obesity. However, the underlying mechanisms are not completely understood. To investigate whether the gut microbiota affects hypothalamic and brainstem body fat-regulating circuits, we compared gene expression of food intake-regulating neuropeptides between germ-free and conventionally raised (CONV-R) mice. We found that CONV-R mice had decreased expression of the antiobesity neuropeptide glucagon-like peptide-1 (GLP-1) precursor proglucagon (Gcg) in the brainstem. Moreover, in both the hypothalamus and the brainstem, CONV-R mice had decreased expression of the antiobesity neuropeptide brain-derived neurotrophic factor (Bdnf). CONV-R mice had reduced expression of the pro-obesity peptides neuropeptide-Y (Npy) and agouti-related protein (Agrp), and increased expression of the antiobesity peptides proopiomelanocortin (Pomc) and cocaine- and amphetamine-regulated transcript (Cart) in the hypothalamus. The latter changes in neuropeptide expression could be secondary to elevated fat mass in CONV-R mice. Leptin treatment caused less weight reduction and less suppression of orexigenic Npy and Agrp expression in CONV-R mice compared with germ-free mice. The hypothalamic expression of leptin resistance-associated suppressor of cytokine signaling 3 (Socs-3) was increased in CONV-R mice. In conclusion, the gut microbiota reduces the expression of 2 genes coding for body fat-suppressing neuropeptides, Gcg and Bdnf, an alteration that may contribute to fat mass induction by the gut microbiota. Moreover, the presence of body fat-inducing gut microbiota is associated with hypothalamic signs of Socs-3-mediated leptin resistance, which may be linked to failed compensatory body fat reduction.
authors.affiliation: Sahlgrenska Academy at the University of Gothenburg, Institute of Neuroscience and Physiology/Endocrinology Medicinaregatan 11, Goteborg-41390, Sweden. john-olov.jansson@medic.gu.se.
authors.forename: Erik
authors.initials: E
authors.lastname: Schéle
authors.forename: Louise
authors.initials: L
authors.lastname: Grahnemo
authors.forename: Fredrik
authors.initials: F
authors.lastname: Anesten
authors.forename: Anna
authors.initials: A
authors.lastname: Hallén
authors.forename: Fredrik
authors.initials: F
authors.lastname: Bäckhed
authors.forename: John-Olov
authors.initials: JO
authors.lastname: Jansson
mesh_terms: D050154:Adiposity; D054369:Agouti-Related Protein / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001933:Brain Stem / Q000378:metabolism; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism*; D002490:Central Nervous System / Q000378:metabolism*; D015536:Down-Regulation; D005856:Germ-Free Life; D007031:Hypothalamus / Q000378:metabolism; D007274:Injections, Intraperitoneal; D007422:Intestines / Q000382:microbiology*; D020738:Leptin / Q000008:administration & dosage / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000378:metabolism*; D009478:Neuropeptide Y / Q000235:genetics / Q000378:metabolism; D011333:Pro-Opiomelanocortin / Q000235:genetics / Q000378:metabolism; D052336:Proglucagon / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000378:metabolism; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000235:genetics / Q000378:metabolism; D000098882:Cocaine- and Amphetamine-Regulated Transcript Protein
chemical_list: D054369:Agouti-Related Protein; C515199:Agrp protein, mouse; D019208:Brain-Derived Neurotrophic Factor; D020738:Leptin; D009419:Nerve Tissue Proteins; D009478:Neuropeptide Y; D011994:Recombinant Proteins; C491411:Socs3 protein, mouse; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D000098882:Cocaine- and Amphetamine-Regulated Transcript Protein; D052336:Proglucagon; D011333:Pro-Opiomelanocortin