J.H. 29 Seo) and eyha@dsmc.or.kr (E. Ha). 30 31 32 33 34 35 Running headline: Pnx regulates thermogenesis and lipogenesis 2 36 Abstract37 This study was designed to determine the effects of pineal gland-derived melatonin on obesity 38 by employing rat pinealectomy (Pnx) model. After 10 weeks of high-fat diet (HFD) feeding, 39 rats received sham or Pnx surgery followed by 10 weeks normal chow diet (NCD) feeding.40 Pnx decreased expressions of melatonin receptors, MTNR1A and MTNR1B, in brown (BAT) 41 and white adipose tissues (WAT). Pnx rats showed increased insulin sensitivity compared 42 with those that received sham surgery. Leptin levels were significantly decreased in the serum 43 of Pnx group. In addition, Pnx stimulated thermogenic genes in BAT whereas attenuated 44 lipogenic genes in WAT and the liver. Histologic analyses revealed marked decreased in the 45 size of lipid droplets and increased expressions of UCP1 in BAT and attenuated lipid droplets 46 in the sized and the number in the liver of Pnx group. In conclusion, these results in the 47 current study suggest that Pnx increases thermogenesis in BAT and decreases lipogenesis in 48 WAT and the liver. 49 50 51 Key Words 52 pinealectomy 53 melatonin 54 brown adipose tissue 55 thermogenesis 56 lipogenesis 57 3 58 Introduction59 Overweight and obesity have been everyday issues for the past decades and statistics proves 60 that they are on a continuous rise worldwide [1]. Obesity is a metabolic syndrome that is 61 associated with a cluster of disorders, ranging from type 2 diabetes mellitus, hypertension and 62 fatty liver disorder [2][3][4]. Despite the increasing life expectancy in the United States, babies 63 born at the beginning of the twenty-first century are predicted to be the first generation that 64 may have shorter life expectancies than their parents [5]. Many of the risk factors for the 65 overweight and obesity are well defined, but the underlying pathogenesis is not well understood.66 At present, therapy is aimed at modifying the risk factors, but there are no sustainable therapies 67 for the prevention or even treatment of obesity.
68Melatonin is a pineal gland-synthesized neurohormone [6]. It exerts its functions via 69 membrane and nuclear receptors as well as receptor-independent actions. Receptor-mediated 70 neuroendocrine functions of melatonin include the circadian rhythm, sleep, the stress response, 71 the process of aging, and immunity [7,8]. Antioxidant effect of melatonin is a well-established 72 receptor-independent function [9].
73Of various functions of melatonin, melatonin promotes energy homeostasis regulating 74 energy balance [10]. Evidences show that melatonin is involved in the regulation of food intake, 75 energy storage, and energy expenditure [11,12]. Melatonin treatment in drinking water or liquid 76 diet reduces body weight and abdominal fat in rats independently of food intake reduction [13-77 16]. In the zebrafish, melatonin inhibits appetite and stimulates satiety signals in the central 78 nervous syst...