title: High-Fat Diet-Induced Obesity Ablates Gastric Vagal Afferent Circadian Rhythms.
abstract: Rats with high-fat diet (HFD)-induced obesity increase daytime eating, suggesting an alteration in circadian food intake mechanisms. Gastric vagal afferents (GVAs) respond to mechanical stimuli to initiate satiety. These signals are dampened in HFD mice and exhibit circadian variations inversely with food intake in lean mice. Furthermore, leptin shows circadian variation in its circulating level and is able to modulate GVA mechanosensitivity. However, whether leptin's ability to modulate GVAs occurs in a circadian manner is unknown. Therefore, we investigated whether changes in the circadian intake of food in HFD-induced obesity is associated with a disruption in GVA circadian rhythms. Eight-week-old male C57BL/6 mice were fed a standard laboratory diet (SLD) or a HFD for 12 weeks. A subgroup of SLD and HFD mice were housed in metabolic cages. After 12 weeks, ex vivo GVA recordings were taken at 3 h intervals starting at zeitgeber time 0 (ZT0) and stomach content was measured. After 12 weeks, HFD mice consumed more food during the light phase through larger and more frequent meals compared with SLD mice. SLD mice exhibited circadian fluctuation in stomach content, which peaked at ZT18 and reached a nadir at ZT9. At these time points, both tension and mucosal receptor mechanosensitivity were the lowest and highest, respectively. HFD mice exhibited little circadian variation in stomach content or GVA mechanosensitivity. Leptin potentiated mucosal receptor mechanosensitivity only in SLD mice and with reduced potency during the dark phase. In conclusion, loss of circadian variation in GVA signaling may underpin changes in eating behavior in HFD-induced obesity.
  
  
  CONCLUSIONS
  Appropriate circadian control of food intake is vital for maintaining metabolic health. Diet-induced obesity is associated with strong circadian changes in food intake, but the contributing mechanisms have yet to be determined. Vagal afferents are involved in regulation of feeding behavior, particularly meal size, and have been shown to exhibit circadian fluctuation in mechanosensitivity, potentially allowing for time of day-specific levels of satiety signaling. Our study indicates that, in diet-induced obesity, these circadian fluctuations in gastric vagal afferent mechanosensitivity are lost. This was accompanied by increased light phase eating, particularly increased meal size. This is the first evidence that diet-induced disruption to vagal afferent signaling may cause a perturbation in circadian eating patterns.
authors.affiliation: Discipline of Medicine and South Australian Health and Medical Research Institute, North Terrace, Adelaide, South Australia 5000, Australia, stephen.kentish@adelaide.edu.au amanda.page@adelaide.edu.au.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Kentish
authors.affiliation: Discipline of Medicine and Freemasons Foundation Centre for Men's Health, The University of Adelaide, Adelaide, South Australia 5005, Australia, South Australian Health and Medical Research Institute, North Terrace, Adelaide, South Australia 5000, Australia.
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Vincent
authors.affiliation: Robinson Research Institute, Discipline of Obstetrics and Gynaecology, University of Adelaide, Adelaide, South Australia 5006, Australia, and.
authors.forename: David J
authors.initials: DJ
authors.lastname: Kennaway
authors.affiliation: Discipline of Medicine and Freemasons Foundation Centre for Men's Health, The University of Adelaide, Adelaide, South Australia 5005, Australia, South Australian Health and Medical Research Institute, North Terrace, Adelaide, South Australia 5000, Australia.
authors.forename: Gary A
authors.identifier: http://orcid.org/0000-0001-6818-6065
authors.initials: GA
authors.lastname: Wittert
authors.affiliation: Discipline of Medicine and South Australian Health and Medical Research Institute, North Terrace, Adelaide, South Australia 5000, Australia, Royal Adelaide Hospital, North Terrace, Adelaide, South Australia 5000, Australia stephen.kentish@adelaide.edu.au amanda.page@adelaide.edu.au.
authors.forename: Amanda J
authors.initials: AJ
authors.lastname: Page
mesh_terms: D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000344:Afferent Pathways / Q000502:physiology; D000818:Animals; D001835:Body Weight / Q000502:physiology; D056926:CLOCK Proteins / Q000378:metabolism; D002940:Circadian Rhythm / Q000502:physiology*; D059305:Diet, High-Fat / Q000009:adverse effects*; D004195:Disease Models, Animal; D004435:Eating / Q000187:drug effects / Q000502:physiology; D004734:Energy Metabolism / Q000502:physiology; D054439:Ghrelin / Q000494:pharmacology; D020738:Leptin / Q000494:pharmacology; D008297:Male; D008465:Mechanoreceptors / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D009765:Obesity / Q000209:etiology* / Q000378:metabolism; D010812:Physical Stimulation; D051381:Rats; D013270:Stomach / Q000294:innervation*; D014630:Vagus Nerve / Q000187:drug effects / Q000473:pathology / Q000502:physiology*
chemical_list: D054439:Ghrelin; D020738:Leptin; D056926:CLOCK Proteins; C538944:Clock protein, mouse
keywords: circadian; food intake; leptin; obesity; stomach; vagus