Anorexic behavior and elevation of hypothalamic malonyl-CoA in socially defeated rats
Highlights
► Socially defeated rats showed suppressed body weight gain. ► Socially defeated rats showed decreased food intake during the dark phase. ► Elevation of hypothalamic malonyl-CoA was observed in socially defeated rats. ► Anorexia under social stress may be involved in hypothalamic malonyl-CoA.
Introduction
Depression is a major mental disorder; approximately 20% of the population is afflicted with depression [1]. Eating disorders, such as anorexia, are one of the major symptoms of depression [2], [3]. Researchers have developed various types of depression-like animal models that are exposed to aversive psychological, physical or chemical stimuli, including social defeat, restraint, forced swimming, corticosterone administration, and mitogen-activated protein kinase inhibition [4], [5], [6], [7], [8]. The suppression of body weight gain has been reported in animal models of depression that are exposed to the stresses mentioned above [4], [5], [6], [7], [8]. Conversely, some animal models of depression showed unchanged or increased body weight gain [9], [10]. Weight loss and reduced appetite are some of the criteria for diagnosing a major depression episode in DSM-IV [2]. However, the mechanisms of weight loss and reduced appetite in depressive patients and in animal models of depression are largely unknown.
Energy homeostasis is regulated by the central nervous system, in particular the hypothalamus. Many neuropeptides that control food intake are expressed in the hypothalamus, for example, orexigenic peptides (agouti-related protein (AgRP), melanin-concentrating hormone (MCH), and neuropeptide Y (NPY)) and anorexigenic peptides (proopiomelanocortin (POMC) and cocaine- and amphetamine-regulated transcript (CART)). Malonyl-coenzyme A (CoA) regulates food intake via the control of neuropeptides, including those described above, in the hypothalamus [11], [12]. Malonyl-CoA is known to intermediate the fatty acid biosynthetic pathway and is synthesized from acetyl-CoA by acetyl-CoA carboxylase (ACC). ACC is phosphorylated and inactivated by phosphorylated AMP-activated protein kinase (AMPK) [11], [12]. The injection of C75, a fatty acid synthase inhibitor, induced an elevation of malonyl-CoA in the hypothalamus and an inhibition of food intake [13]. Thus, malonyl-CoA functions as a master mediator in the hypothalamus that controls feeding behavior.
In this study, we investigate the mechanism of anorexia in depression using socially defeated rats, with a particular focus on the malonyl-CoA signaling pathway in the hypothalamus.
Section snippets
Animals
Our detailed experimental design has been described previously [14]. Eight-week-old male Wistar rats were purchased from Charles River (Yokohama, Japan) and were housed individually at room temperature (22 ± 1 °C), with exposure to light from 6:00 to 18:00 and ad libitum access to food and water. After arrival, the rats were handled daily for 1 week to habituate them to the environment; they were then used as intruders. Twelve-week-old male Wistar rats from our colonies were used as residents. Each
Results
In this study, the stress group showed a suppression in body weight gain compared to the control group as our previous study (Fig. 1A) [14]. Prior to stress exposure, the body weights of the stress and the control groups were similar (294.8 ± 4.9 g vs. 301.2 ± 3.7 g, p > 0.1). A two-way repeated measures ANOVA revealed that stress had a significant effect on body weight gain (F (1, 78) = 33.78, p < 0.001), and the stress × time interaction was significant (F (6, 78) = 23.66, p < 0.001). Subsequently, Bonferroni
Discussion
In this study, we exposed rats daily to social defeat stress for 5 weeks. Our results demonstrated that chronic social defeat stress induced physiological, behavioral, and molecular changes. A suppression in body weight gain is one of the criteria used to diagnose major depression in humans and has been reported in previous studies using animal models of depression [2], [4], [5], [6], [7], [8]. We observed that socially defeated rats also show a suppression in body weight gain compared to the
Acknowledgments
We would like to thank Dr. Hiroko Toyoda (Ibaraki University) for helpful comments regarding the manuscript. This research was supported in part by Grants-in-Aid No.22580303 to A.T., No.23126501 to S.C. and No.22935009 to N.M. from the Ministry of Education, Culture, Sports, Science and Technology of Japan.
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