Neuropeptides. 2014 Jun; 48(3): 119-132

Regulation of expression of relaxin-3 and its receptor RXFP3 in the brain of diet-induced obese rats

Lenglos C, Mitra A, Guèvremont G, Timofeeva E.

Département Psychiatrie et Neurosciences, Faculté de Médecine, Université Laval, Québec (QC), G1V 4G5, Canada

 

Abstract

An animal model closely related to human obesity is diet-induced obesity in Sprague-Dawley rats. These rats placed on a high-energy (HE) diet show wide distribution in body weight gain with a subset of animals developing diet-induced obesity (DIO) and the remaining animals showing a diet-resistant (DR) phenotype. Once obesity is established, DIO rats strongly defend their increased body weight against caloric restriction. There is evidence that neuropeptide relaxin-3 is involved in food intake regulation, but the levels of expression of relaxin-3 and its receptor have not been yet demonstrated in the DIO model. The present study investigated the brain expression of relaxin-3 and its cognate receptor RXFP3 in DIO and DR rats maintained on an HE diet since weaning. Expression of relaxin-3 and RXFP3 mRNAs was assessed by in situ hybridization in ad libitum, food-deprived (12 h) and refed (1 h) feeding states. The levels of expression of relaxin-3 in the medial portion of the nucleus incertus (NI) were higher in the DIO rats compared to the DR rats in the ad libitum-fed state. Food deprivation increased the levels of expression of relaxin-3 in the medial NI in DR but not DIO rats. The stronger expression of relaxin-3 in the ad libitum-fed state in the DIO rats was accompanied by low expression of the RXFP3 receptor in the paraventricular hypothalamic nucleus (PVN), supraoptic nucleus, central amygdala (CeA), NI, and nucleus of the solitary tract (NTS). Refeeding increased expression of RXFP3 in the paraventricular thalamic nucleus, parvocellular PVN, CeA, NI, and NTS in the DIO rats. These results provide evidence that DIO rats show a constitutive increase in relaxin-3 expression in the medial NI and that refeeding after food deprivation may enhance the orexigenic effects of relaxin-3 in DIO rats by rapid upregulation of the expression of RXFP3 in the specific brain regions involved in food intake regulation.

PMID: 24629399

 

Supplement:

Incidence of overweight and obesity has dramatically increased throughout the world during the past few decades. Treatments of this serious clinical problem are hindered by the fact that once obesity has developed, the elevated body weight is defended against weight-decreasing treatment strategies by mechanisms that are not yet fully understood. The dietary therapy remains the first-line treatment for overweight and obese patients. However, short-term weight loss produced by dietary restriction is difficult to maintain. Moreover, for one to two thirds of dieters calorie-restricted diets are counterproductive because in the long-term the patients regain more weight than they lose on their diets. The difficulty to maintain body weight loss suggests functioning of mechanisms that strongly defend elevated body weight in obese patients. Among the neuronal factors regulating energy intake, orexigenic neuropeptide relaxin-3 and its specific receptor RXFP3 may play an important role in defense of elevated body weight (Fig. 1).

Fig_1

Fig 1. Defense of elevated body weight in diet-induced obesity.

 

Relaxin-3 is expressed in the brainstem nucleus incertus (NI) from where relaxin-3 is transported to the forebrain structures expressing RXFP3 (1, 2) (Fig. 2). Central administration of relaxin-3 or RXFP3 receptor agonists strongly stimulated feeding and increased fat accumulation and body weight gain in rats (3, 4, 8). Expression of relaxin-3 in the NI was significantly increased in female hyperphagic rats with a history of repeated food restriction and stress (5).

Fig_2
Fig 2. Expression of relaxin-3 and its specific receptor RXFP3 in diet-induced obese (DIO) rats. DIO rats showed higher expression of relaxin-3 in the nucleus incertus (NI) compared to diet-resistant (DR) rats under free feeding conditions and during refeeding after food deprivation. The expression of the specific relaxin-3 receptor RXFP3 was lower in DIO rats in the majority of brain regions under free feeding conditions. In contrast, during refeeding after food deprivation expression of RXFP3 significantly increased in the DIO rats. CeA – central nucleus of amygdala; NTS – nucleus of the solitary tract; PVNp – parvocellular paraventricular hypothalamic nucleus; PVT – parvocellular thalamic nucleus.

 

The results obtained in our laboratory have shown higher expression of relaxin-3 in the NI of the diet-induced obese (DIO) rats compared to diet-resistant (DR) rats. DIO rats, but not DR rats, develop obesity, hyperinsulinemia, and dyslipidemia on high-energy diet. Once the DIO phenotype is established, it is strongly defended. Obesity persisted in DIO rats even when animals were returned back to a low-energy diet (6). To lose body weight, the DIO rats have to be forcibly food restricted; however they rapidly regained body weight during refeeding after food deprivation (7).

The orexigenic effects of relaxin-3 in DIO rats under free feeding conditions seem to be compensated by a decrease in the levels of expression of RXFP3 in the food intake-regulating brain regions (Fig. 2). Simultaneously increased expression of relaxin-3 and decreased expression of RXFP3 in free-feeding conditions may play a role in maintenance of reached plateau in elevated body weight set point in diet-induced obesity (Fig. 3). Remarkably, after a period of food deprivation, the DIO rats showed an immediate rebound in food intake at refeeding and regained all body weight lost during starvation. This significant increase in food intake during refeeding was accompanied by an increase in the levels of expression of RXFP3 in the key brain regions regulating appetite and energy metabolism (Fig. 2). Synergistic increase in expression of relaxin-3 and its specific receptor RXFP3 during eating after food restriction may contribute to increased appetite and feed efficiency in DIO rats (Fig. 3) and represent a powerful mechanism of defense of elevated body weight set point in diet-induced obesity.

Fig_3

Figure 3. The effects of increased relaxin-3 expression in the diet-induced obese (DIO) rats are balanced by a decrease in expression of the specific relaxin-3 receptor RXFP3 under free-feeding conditions. Conversely, during eating after food deprivation, expression of RXFP3 is significantly increased in DIO rats that enhances the orexigenic effects of relaxin-3 and helps to defend elevated body weight against caloric restriction.

 

References

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Acknowledgements: This study was supported by CIHR Operating Grant 126123 and NSERC Discovery Grant 327597 awarded to Elena Timofeeva.

Contact:

Elena Timofeeva, Ph.D.

Associate Professor

Dep. Psychiatry and Neuroscience

Laval University

Québec, Canada, G1V0A6

Elena.Timofeeva@fmed.ulaval.ca

http://timofeeva-stress-feeding-lab.ca/

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