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Effects of Chronic Intracerebroventricular Infusion of RFamide-Related Peptide-3 on Energy Metabolism in Male Mice.

ABSTRACT: RFamide-related peptide-3 (RFRP-3), the mammalian ortholog of avian gonadotropin-inhibitory hormone (GnIH), plays a crucial role in reproduction. In the present study, we explored the other functions of RFRP-3 by investigating the effects of chronic intracerebroventricular infusion of RFRP-3 (6 nmol/day) for 13 days on energy homeostasis in lean male C57BL/6J mice. The infusion of RFRP-3 increased cumulative food intake and body mass. In addition, the masses of brown adipose tissue (BAT) and the liver were increased by the administration of RFRP-3, although the mass of white adipose tissue was unchanged. On the other hand, RFRP-3 decreased O₂ consumption, CO₂ production, energy expenditure, and core body temperature during a short time period in the dark phase. These results suggest that the increase in food intake and the decrease in energy expenditure contributed to the gain of body mass, including the masses of BAT and the liver. The present study shows that RFRP-3 regulates not only reproductive function, but also energy metabolism, in mice.

SUBMITTER: Moriwaki S

PROVIDER: S-EPMC7698077 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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Effects of Chronic Intracerebroventricular Infusion of RFamide-Related Peptide-3 on Energy Metabolism in Male Mice.

Moriwaki Shogo S Narimatsu Yuki Y Fukumura Keisuke K Iwakoshi-Ukena Eiko E Furumitsu Megumi M Ukena Kazuyoshi K

International journal of molecular sciences 20201115 22

RFamide-related peptide-3 (RFRP-3), the mammalian ortholog of avian gonadotropin-inhibitory hormone (GnIH), plays a crucial role in reproduction. In the present study, we explored the other functions of RFRP-3 by investigating the effects of chronic intracerebroventricular infusion of RFRP-3 (6 nmol/day) for 13 days on energy homeostasis in lean male C57BL/6J mice. The infusion of RFRP-3 increased cumulative food intake and body mass. In addition, the masses of brown adipose tissue (BAT) and the ...[more]

PMID: 33203104

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Project description:RATIONALE:Effort-related choice tasks are used to study aspects of motivation in both rodents and humans (Der-Avakian and Pizzagalli Biol Psychiatry 83(11):932-939, 2018). Various dopaminergic manipulations and antidepressant treatments can shift responding to these tasks (Randall et al. Int J Neuropsychopharmacol 18(2), 2014; Yohn et al. Psychopharmacology 232(7):1313-1323, 2015). However, while chronic stress can precipitate mood disorders in humans, there is relatively little known about whether chronic stress elicits maladaptive behaviors in rodent effort-related choice tasks. OBJECTIVES:Chronic corticosterone (CORT) elicits an increase in negative maladaptive behaviors in male mice (David et al. Neuron 62(4):479-493, 2009; Gourley et al. Biol Psychiatry 64(10):884-890, 2008; Olausson et al. Psychopharmacology 225(3):569-577, 2013). We hypothesized that chronic CORT administration to male mice would reduce motivation for a higher effort, higher reward option, and shift responding to a less effortful, but a lesser reward. METHODS:Adult male C57BL/6J mice were administered either vehicle (n = 10) or CORT (n = 10) (~ 9.5 mg/kg/day) in their drinking water for 4 weeks, and then throughout all behavioral experiments (15 weeks total), and were tested in a Y-Maze barrier task and a fixed ratio concurrent (FR/chow) choice task. RESULTS:Chronic CORT reduced Y-maze HR arm choice when more effort was required to obtain the 4 food pellets (15-cm barrier in the high-reward (HR) arm, p < 0.001; 20-cm barrier in HR arm, p < 0.001) and shifted choice to the low reward (LR) arm where only 2 pellets were available. Chronic CORT also reduced lever pressing for food pellets in FR30/chow sessions of the concurrent choice task (p = 0.009), without impacting lab chow consumed. CONCLUSIONS:Chronic stress induces maladaptive shifts in effort-related choice behavior in the Y-maze barrier task in male mice. Furthermore, males subjected to chronic CORT administration show reduced lever pressing in FR30/chow sessions where lab chow is concurrently available. These data demonstrate that chronic corticosterone reduces motivation to work for and obtain a highly rewarding reinforcer when a lesser reinforcer is concurrently available.

Project description:ContextPHEX or DMP1 mutations cause hypophosphatemic-rickets and altered energy metabolism. PHEX binds to DMP1-ASARM-motif to form a complex with ?5?3 integrin that suppresses FGF23 expression. ASARM-peptides increase FGF23 by disrupting the PHEX-DMP1-Integrin complex. We used a 4.2 kDa peptide (SPR4) that binds to ASARM-peptide/motif to study the DMP1-PHEX interaction and to assess SPR4 for the treatment of energy metabolism defects in HYP and potentially other bone-mineral disorders.DesignSubcutaneously transplanted osmotic pumps were used to infuse SPR4-peptide or vehicle (VE) into wild-type mice (WT) and HYP-mice (PHEX mutation) for 4 weeks.ResultsSPR4 partially corrected HYP mice hypophosphatemia and increased serum 1.25(OH)2D3. Serum FGF23 remained high and PTH was unaffected. WT-SPR4 mice developed hypophosphatemia and hypercalcemia with increased PTH, FGF23 and 1.25(OH)2D3. SPR4 increased GAPDH HYP-bone expression 60× and corrected HYP-mice hyperglycemia and hypoinsulinemia. HYP-VE serum uric-acid (UA) levels were reduced and SPR4 infusion suppressed UA levels in WT-mice but not HYP-mice. SPR4 altered leptin, adiponectin, and sympathetic-tone and increased the fat mass/weight ratio for HYP and WT mice. Expression of perlipin-2 a gene involved in obesity was reduced in HYP-VE and WT-SPR4 mice but increased in HYP-SPR4 mice. Also, increased expression of two genes that inhibit insulin-signaling, ENPP1 and ESP, occurred with HYP-VE mice. In contrast, SPR4 reduced expression of both ENPP1 and ESP in WT mice and suppressed ENPP1 in HYP mice. Increased expression of FAM20C and sclerostin occurred with HYP-VE mice. SPR4 suppressed expression of FAM20C and sclerostin in HYP and WT mice.ConclusionsASARM peptides and motifs are physiological substrates for PHEX and modulate osteocyte PHEX-DMP1-?5?3-integrin interactions and thereby FGF23 expression. These interactions also provide a nexus that regulates bone and energy metabolism. SPR4 suppression of sclerostin and/or sequestration of ASARM-peptides improves energy metabolism and may have utility for treating familial rickets, osteoporosis, obesity and diabetes.

Dataset Information

Effects of Chronic Intracerebroventricular Infusion of RFamide-Related Peptide-3 on Energy Metabolism in Male Mice.

Publications

Effects of Chronic Intracerebroventricular Infusion of RFamide-Related Peptide-3 on Energy Metabolism in Male Mice.

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