The GhsrQ343X allele favors the storage of fat by acting on nutrient partitioning

in Journal of Endocrinology
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  • 1 Université de Paris, INSERM UMR S-1124, CNRS ERL3649, Paris, France
  • | 2 Université de Bordeaux, Neurocentre Magendie, INSERM U1215, Bordeaux, France
  • | 3 Université de Paris, BFA, UMR 8251, CNRS, Paris, France
  • | 4 Université de Paris, Institute of Psychiatry and Neuroscience of Paris (IPNP), INSERM U1266, Laboratoire de Physiopathologie des Maladies Psychiatriques, Paris, France

Correspondence should be addressed to J Pantel: jacques.pantel@inserm.fr

*(C Marion and P Zizzari contributed equally to this work)

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The growth hormone secretagogue receptor (GHSR) mediates key properties of the gut hormone ghrelin on metabolism and behavior. Nevertheless, most recent observations also support that the GHSR is a constitutively active G protein-coupled receptor (GPCR) endowed with a sophisticated tuning involving a balance of endogenous ligands. Demonstrating the feasibility of shifting GHSR canonical signaling in vivo, we previously reported that a model with enhanced sensitivity to ghrelin (GhsrQ343X mutant rats) developed fat accumulation and glucose intolerance. Herein, we investigated the contribution of energy homeostasis to the onset of this phenotype, as well as behavioral responses to feeding or pharmacological challenges, by comparing GhsrM/M rats to WT littermate rats: (1) as freely behaving animals and (2) in feeding and locomotor paradigms. Herein, GhsrM/M rats showed enhanced locomotor response to a GHSR agonist while locomotor or anorexigenic responses to amphetamine or cabergoline (dopamine receptor 2 agonist), respectively, were preserved. Ad libitum fedGhsrM/M rats consumed and conditioned for sucrose similarly to littermate control rats . In calorie-restricted conditions, GhsrM/M rats retained food anticipatory activity and maintained better body weight and glycemia. Importantly, prior to fat accumulation, male GhsrM/M rats preferentially used carbohydrates as fuel substrate without alterations of energy intake, energy expenditure or physical activity and showed alterations of the GHSR system (i.e. enhanced ratio of GHSR hormones LEAP2: acyl-ghrelin and increased Ghsr expression in the hypothalamus). Overall, the present study provides proof for the concept that shifted GHSR signaling can specifically alter nutrient partitioning resulting in modified balance of carbohydrate/lipid utilization.

Supplementary Materials

    • Supplementary Figure 1: Glycemia fluctuations across feeding conditions. GhsrM/M and GhsrWT/WT male rats at 15 weeks of age (n=6-8/genotype). Data represent mean ± SEM.
    • Supplementary Figure 2: Diurnal and nocturnal meal patterns of Ghsr<sup>M/M</sup> and Ghsr<sup>WT/WT</sup> rats during ad libitum-feeding and refeeding. (A-B) Mean meal size during light (A) and dark (B) phases. (C-D) Total chow ingested during light (C) and dark (D) phases. (E-F) Total time spent eating during light (E) and dark (F) phases. (G-H) Number of meals during light (G) and dark (H) phases. (I-J) Mean meal duration in light (I) and dark (J) phases. (K-L) Inter-meal interval during light (K) and dark (L) phases. (M-N) Meal ingestion rate in light (M) and dark (N) phases (n=12/genotype). Data represent mean ± SEM.
    • Supplementary Figure 3: Decreased fat oxydation in Ghsr<sup>M/M</sup> rats across feeding conditions. (A-C) Daily pattern of fat oxydation during adlibitum feeding (A), 24h fasting (B) and 24h refeeding (C). Data represent mean ± SEM. (D) 24-h cumulative fat oxydation (n=12/genotype). Data were analyzed by 2-way ANOVA (E) Relative cumulative frequency curves for ad libitum fed Ghsr<sup>M/M</sup> and Ghsr<sup>WT/WT</sup> rats (dots) and curve fits (full lines) reveal higher EC50 (0.947 vs. 0.933) and a lower 1/Hill slope value (0.067 vs. 0.074) for GhsrM/M rats compared to GhsrWT/WT rats (F-test; p<0.001 for both parameters). * p<0.05; *** p<0.001.
    • Supplementary Materials
    • Supplementary Table 1. Primers sequence for real time PCR analysis
    • Supplementary Table 2. House keeping gene primers sequence for real time PCR analysis

 

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