Diet-induced obesity impacts mRNA expression in hypoglossal motoneurons in mice

Abstract

Obstructive sleep apnea (OSA) is characterized by loss of airway patency during sleep. OSA prevalence in obese patients is approximately double that of normal weight patients, as noted in humans, rats, pigs, and brachycephalic dogs. Leptin is normally transported from the periphery across the blood brain barrier (BBB) where it acts in the central nervous system (CNS) to activate ion channels in neurons. Peripheral hyperleptinemia associated with obesity saturates and downregulates leptin transport proteins at the BBB leading to a state of relative leptin deficiency in the CNS. This relative deficiency may be partially responsible for OSA because, regardless of weight, OSA patients have plasma leptin levels 50% higher than controls, with disease severity proportional to the degree of hyperleptinemia. Thus, we hypothesize that dysregulated leptin signaling in the CNS may contribute to loss of tongue muscle tone via ion channels dysfunction in the hypoglossal motoneurons (XII MNs) that innervate the tongue. To test our hypothesis that disrupted leptin signaling contributes to the loss of XII MN activity, we fed 12 male and 12 female CD1 mice and litter-matched controls a high-fat diet (HFD) for 16 weeks starting at 3-5 weeks old. Mice fed a HFD gained more weight than control mice (M: 45±12 vs 27±7 g, F: 34±18 vs 22±12 g, HFD vs control, p < 0.05), had increased visceral fat pad mass (M: 8±5 vs 3±2 g, F: 12±5 vs 3±2 g, HFD vs control, p < 0.05) and were more likely to have hepatic lipidosis (M: 10/11 vs 0/12, F: 8/11 vs 0/12, HFD vs control, p < 0.05). Surprisingly, male fed a HFD did not have significantly increased serum leptin levels compared to controls (8301±4053 vs 4392±3408 pg/ml, p > 0.05), while female fed a HFD did (7504±5327 vs 2842±4277 pg/ml, p < 0.05). Obesity is also associated with increased inflammation, thus serum inflammatory markers TNFα (M: 13±7 vs 9±7 pg/ml, F: 16±9 vs 10±7 pg/ml, p < 0.05) as well as IL-6 (M: 152±122 vs 65±34 pg/ml, F: 143±122 vs 57±25 pg/ml, p < 0.05) were significantly higher in HFD compared to control mice. RNA sequencing from 10 HFD and 10 control brainstem slices containing XII MNs uncovered significant (p < 0.1) upregulation of 6 genes and downregulation of 9 genes including DnaJ heat shock protein family member B12 (Dnajb1), nuclear paraspeckle assembly transcript 1 (Neat1), ankyrin 2 (Ank2), low density lipoprotein receptor-related protein (Lrp1), and ryanodine receptor (RyR2). These genetic changes suggest disrupted ion channel function as well as neuronal stress. Future research will evaluate the functional effects of these genetic changes to elucidate mechanistic links between obesity, leptin signaling and OSA onset. Midwestern University One Health Grant Student Award (Myers), Midwestern University One Health Grant Faculty Award (Vallejo, Revill, Bussey), Boehringer Ingelheim Veterinary Scholars Program (Myers) This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.