Reduced fasting-induced activation of hypothalamic arcuate neurons is associated with hyperleptinemia and increased leptin sensitivity in obese mice.
Fasting increases c-Fos expression in neuropeptide Y (NPY) neurons of the hypothalamic arcuate nucleus (ARC) in lean, but not in hyperleptinemic mice with late-onset obesity (LOO). Although obesity is associated with leptin resistance, we hypothesized that under fasting conditions, leptin sensitivity might be restored and that hyperleptinemia may counteract the neuronal response to fasting. We investigated whether the reduced fasting response of ARC neurons in LOO is paralleled by an increase in leptin sensitivity, as measured by leptin-induced STAT-3 phosphorylation. To assess leptin's role in the modulation of the fasting-induced ARC activation, we investigated c-Fos responses and hormone and metabolite levels in hyperleptinemic diet-induced obese (DIO) and in leptin-deficient ob/ob mice. Leptin induced a stronger STAT-3 phosphorylation in fasted LOO and lean mice than in ad libitum-fed animals. Similar to LOO, hyperleptinemic DIO mice showed no c-Fos response after fasting, while ob/ob mice showed a stronger response than lean control mice. Mimicking hyperleptinemia by repeated leptin injections in lean mice during fasting attenuated the fasting-induced c-Fos expression. Our findings indicate that high leptin levels prevent the fasting-induced activation of ARC neurons in mice. Moreover, leptin sensitivity is dynamic in obese subjects and depends on the feeding status. During short-term increases in leptin sensitivity, e.g., during fasting, leptin signaling appears to be effective, even in hyperleptinemic obesity. As reflected by the blockade of the fasting-induced ARC activation, fasting seems to interfere with the responsiveness of the ARC to signals related to the status of energy intake.
Institute of Veterinary Physiology and Zurich Centre of Human Integrative Physiology, University of Zurich, Zurich, Switzerland.
Csilla
C
Becskei
Thomas A
TA
Lutz
Thomas
T
Riediger
D020155:3-Hydroxybutyric Acid / Q000097:blood; D000818:Animals; D001111:Arcuate Nucleus of Hypothalamus / Q000378:metabolism* / Q000503:physiopathology; D001786:Blood Glucose / Q000378:metabolism; D004041:Dietary Fats; D004195:Disease Models, Animal; D005215:Fasting / Q000378:metabolism; D005230:Fatty Acids, Nonesterified / Q000097:blood; D054439:Ghrelin / Q000097:blood; D007279:Injections, Subcutaneous; D007328:Insulin / Q000097:blood; D020738:Leptin / Q000008:administration & dosage / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000378:metabolism*; D009765:Obesity / Q000209:etiology / Q000378:metabolism* / Q000503:physiopathology; D010766:Phosphorylation; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D013997:Time Factors
D001786:Blood Glucose; D004041:Dietary Fats; D005230:Fatty Acids, Nonesterified; D054439:Ghrelin; D007328:Insulin; D020738:Leptin; D016760:Proto-Oncogene Proteins c-fos; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D020155:3-Hydroxybutyric Acid