Browning of adipose tissue is induced by specific stimuli such as cold exposure and consists of up-regulation of thermogenesis in white adipose tissue. Recently, it has emerged as an attractive target for managing obesity in humans. Here, we performed a comprehensive analysis to identify genes associated with browning in murine adipose tissue. We focused on glycerol kinase (GYK) because its mRNA expression pattern is highly correlated with that of uncoupling protein 1 (UCP1), which regulates the thermogenic capacity of adipocytes. Cold exposure-induced Ucp1 up-regulation in inguinal white adipose tissue (iWAT) was partially abolished by Gyk knockdown (KD) in vivo. Consistently, the Gyk KD inhibited Ucp1 expression induced by treatment with the β-adrenergic receptors (βAR) agonist isoproterenol (Iso) in vitro and resulted in impaired uncoupled respiration. Gyk KD also suppressed Iso- and adenylate cyclase activator-induced transcriptional activation and phosphorylation of the cAMP response element-binding protein (CREB). However, we did not observe these effects with a cAMP analog. Therefore Gyk KD related to Iso-induced cAMP products. In Iso-treated Gyk KD adipocytes, stearoyl-CoA desaturase 1 (SCD1) was up-regulated, and monounsaturated fatty acids such as palmitoleic acid (POA) accumulated. Moreover, a SCD1 inhibitor treatment recovered the Gyk KD-induced Ucp1 down-regulation and POA treatment down-regulated Iso-activated Ucp1. Our findings suggest that Gyk stimulates Ucp1 expression via a mechanism that partially depends on the βAR-cAMP-CREB pathway and Gyk-mediated regulation of fatty acid metabolism.

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GHRELIN, an endogenous ligand for the growth hormone (GH) secretagogue receptor (GHS-R or ghrelin receptor), is a 28 amino acid-long acylated peptide [1]. It is mainly produced in the stomach, but is also expressed in the upper intestinal tract, pancreas, pituitary, and hypothalamus [1][2][3]. By contrast, the ghrelin receptor, GHS-R 1a, is expressed in the anterior pituitary and hypothalamus, suggesting that ghrelin/GHS-R signaling is involved in energy homeostasis and GH release [4][5][6]. Indeed, peripheral administration of ghrelin Reduction in circulating ghrelin concentration after maturation does not affect food intake Abstract. Ghrelin has a potent orexigenic effect and induces adiposity when administered exogenously. Since plasma ghrelin levels rise before meals, ghrelin was thought to play a crucial role in the regulation of appetite. In contrast, mice deficient in the production of ghrelin or the corresponding receptor, GHS-R, do not eat less, throwing the role of ghrelin in the regulation of energy homeostasis into question. Since these mice lack ghrelin or GHS-R from the time of conception, the possibility that compensatory mechanisms may have arisen during development cannot be ruled out. In this study, we used a transgenic mouse model that expresses human diphtheria toxin (DT) receptor cDNA under the control of the ghrelin promoter (GPDTR-Tg mice). As previously reported, an injection of DT into this mouse model ablates ghrelin-secreting cells in the stomach but not in the hypothalamus, resulting in a reduction in circulating ghrelin levels. We used this model system to evaluate the physiological roles of circulating ghrelin in the regulation of food intake. Meal patterns, diurnal and nocturnal meal sizes, and cumulative food intake of DT-treated GPDTR-Tg mice were not affected, although circulating ghrelin levels markedly decreased even after fasting. These mice also displayed normal responses to starvation; however, the use of fat increased and slower weight gain when maintained on a high fat diet was observed. Together, these data suggest that circulating ghrelin does not play a crucial role in feeding behavior, but rather is involved in maintaining body weight.Key words: Ghrelin, Food intake, Obesity induces not only GH secretion but also increased food intake and adiposity [1,[7][8][9][10]. With respect to feeding behavior, it is reported that a dose of ghrelin that stimulates feeding results in similar circulating ghrelin levels to those detected after a 24 h fast [11]. In addition, plasma ghrelin levels rise during fasting and are rapidly suppressed after feeding [2,12]. These results suggest that ghrelin may be a circulating orexigen, stimulating appetite and meal initiation. Conversely, results showing that mice deficient in ghrelin or its receptor do not decrease food intake imply that ghrelin may not play a critical role in appetite [13][14][15][16].Ghrelin-and GHS-R-deficient mice are not optimal animal models for the evaluation of physiological roles of circulating ghrelin, because th...