title: Sex-related differences in small intestinal transit and serotonin dynamics in high-fat-diet-induced obesity in mice.
abstract: Obesity alters gastrointestinal (GI) motility and 5-HT signalling. Altered 5-HT signalling disrupts control of GI motility. Levels of extracellular 5-HT depend on enterochromaffin (EC) cell release and serotonin transporter (SERT) uptake. We assessed GI transit and 5-HT signalling in the jejunum of normal and obese mice. Male and female mice were fed a control diet (CD; 10% of kilocalories as fat) or a high-fat diet (HFD; 60% of kilocalories as fat). Gastrointestinal transit was increased in male HFD-fed and female CD-fed compared with male CD-fed mice. The 5-HT3 receptor blocker, alosetron, increased gastric emptying in male CD-fed mice, but decreased transit in female CD-fed mice. The 5-HT-induced jejunal longitudinal muscle contractions in vitro were similar in all mice. In contrast to male CD-fed mice, 5-HT uptake (measured using continuous amperometry in vitro) in male HFD-fed mice was fluoxetine insensitive, yet sensitive to cocaine and the dopamine transporter (DAT) blocker GBR 12909. Immunoreactivity for DAT was present in the mucosa, and protein levels were greater in male HFD-fed compared with CD-fed mice. Extracellular 5-HT and mucosal 5-hydroxyindolacetic acid (5-HT metabolite) were similar in male HFD-fed compared with CD-fed mice. 5-Hydroxytryptamine uptake was fluoxetine sensitive in all females. Greater SERT protein, decreased extracellular 5-HT and greater mucosal 5-hydroxyindolacetic acid were observed in female HFD-fed compared with CD-fed mice. Mucosal 5-HT and EC cell numbers were similar in CD-fed and HFD-fed mice of both sexes; female 5-HT and EC cell numbers were increased compared with males. The HFD did not alter plasma sex hormone levels in any mice. Overall, obesity alters GI transit and 5-HT signalling in a sex-dependent manner.
authors.affiliation: Neuroscience Program, Michigan State University, East Lansing, MI, USA.
authors.forename: Marion
authors.initials: M
authors.lastname: France
authors.affiliation: Neuroscience Program, Michigan State University, East Lansing, MI, USA.
authors.forename: Emmalee
authors.initials: E
authors.lastname: Skorich
authors.affiliation: Department of Pediatrics and Human Development, Michigan State University, East Lansing, MI, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Kadrofske
authors.affiliation: Neuroscience Program, Michigan State University, East Lansing, MI, USA.|Department of Chemistry, Michigan State University, East Lansing, MI, USA.
authors.forename: Greg M
authors.initials: GM
authors.lastname: Swain
authors.affiliation: Neuroscience Program, Michigan State University, East Lansing, MI, USA.|Department of Pharmacology & Toxicology, Michigan State University, East Lansing, MI, USA.
authors.forename: James J
authors.initials: JJ
authors.lastname: Galligan
mesh_terms: D000818:Animals; D002243:Carbolines / Q000494:pharmacology; D059305:Diet, High-Fat / Q000009:adverse effects; D005260:Female; D005473:Fluoxetine / Q000494:pharmacology; D005772:Gastrointestinal Transit; D007421:Intestine, Small / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology*; D007583:Jejunum / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009765:Obesity / Q000378:metabolism / Q000503:physiopathology*; D012701:Serotonin / Q000378:metabolism*; D058831:Serotonin 5-HT3 Receptor Antagonists / Q000494:pharmacology; D050486:Serotonin Plasma Membrane Transport Proteins / Q000378:metabolism; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology; D012727:Sex Characteristics
chemical_list: D002243:Carbolines; D005473:Fluoxetine; D012701:Serotonin; D058831:Serotonin 5-HT3 Receptor Antagonists; D050486:Serotonin Plasma Membrane Transport Proteins; D017367:Selective Serotonin Reuptake Inhibitors; C493231:Slc6a4 protein, mouse; C090840:alosetron