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Summary Adipose triglyceride lipase (ATGL) is the rate-limiting enzyme for triacylglycerol (TAG) hydrolysis in adipocytes. The precise mechanisms whereby ATGL is regulated remain uncertain. Here we demonstrate that a protein encoded by G0/G1 switch gene 2 (G0S2) is a selective regulator of ATGL. G0S2 is highly expressed in adipose tissue and differentiated adipocytes. When overexpressed in HeLa cells, G0S2 localizes to lipid droplets and prevents their degradation mediated by ATGL. Moreover, G0S2 specifically interacts with ATGL, requiring the hydrophobic domain of G0S2 and the patatin-like domain of ATGL. More importantly, interaction with G0S2 inhibits the TAG hydrolase activity of ATGL. Furthermore, knockdown of endogenous G0S2 accelerates basal and stimulated lipolysis in adipocytes, while overexpression of G0S2 diminishes the rate of lipolysis in both adipocytes and adipose tissue explants. Thus, G0S2 functions to attenuate ATGL action both in vitro and in vivo, underlying a novel mechanism for the regulation of TAG hydrolysis.

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SummaryThe adipose-derived hormone leptin is well known for its function in the control of energy homeostasis. Recent studies suggest a novel role for this adipokine in the regulation of mood and emotion. Low levels of leptin have been found to be associated with depressive behaviors in rodents and humans. Pharmacological studies indicate that leptin has antidepressant-like efficacy. Both leptin insufficiency and leptin resistance may contribute to alterations of affective status. Identifying the key brain regions that mediate leptin's antidepressant activity and dissecting its intracellular signal transduction pathways may provide new insights into the pathogenesis of depression and facilitate the development of novel therapeutic strategies for the treatment of this illness.

The molecular mechanisms that control the range and stability of emotions are unknown, yet this knowledge is critical for understanding mood disorders, especially bipolar illness. Here, we show that the glucocorticoid receptor (GR) modulates these features of emotional responsiveness. We generated transgenic mice overexpressing GR specifically in forebrain. These mice display a significant increase in anxiety-like and depressant-like behaviors relative to wild type. Yet, they are also supersensitive to antidepressants and show enhanced sensitization to cocaine. Thus, mice overexpressing GR in forebrain have a consistently wider than normal range of reactivity in both positive and negative emotionality tests. This phenotype is associated, in specific brain regions, with increased expression of genes relevant to emotionality: corticotropin-releasing hormone, serotonin, norepinephrine and dopamine transporters, and 5-hydroxytryptamine 1A receptor. Thus, GR overexpression in forebrain causes higher ''emotional lability'' secondary to a unique pattern of molecular regulation. This finding suggests that natural variations in GR gene expression can contribute to the fine-tuning of emotional stability or lability and may play a role in bipolar disorder.

Although glycogen synthase kinase-3 (GSK-3) might act as a tumor suppressor since its inhibition is expected to mimic the activation of Wnt-signaling pathway, GSK-3β may contribute to NF-κB activation in cancer cells leading to increased cancer cell proliferation and survival. Here we report that GSK-3β activity was involved in the proliferation of human ovarian cancer cell both in vitro and in vivo. Inhibition of GSK-3 activity by pharmacological inhibitors suppressed proliferation of the ovarian cancer cells. Overexpressing constitutively active form of GSK-3β induced entry into the S phase, increased cyclin D1 expression and facilitated the proliferation of ovarian cancer cells. Furthermore, GSK-3 inhibition prevented the formation of the tumor in nude mice generated by the inoculation of human ovarian cancer cells. Our findings thus suggest that GSK-3β activity is important for the proliferation of ovarian cancer cells, implicating this kinase as a potential therapeutic target in ovarian cancer.

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Both central alpha-melanocyte-stimulating hormone and corticotropin-releasing hormone (CRH) have been implicated in feeding and neuroendocrine mechanisms. The anatomical overlap and functional similarities between these two neurotransmitter systems led to the hypothesis that CRH might act as one of the mediators of the central actions of the melanocortin system. By double-labeling in situ hybridization, a subpopulation of CRH neurons in the paraventricular nucleus of the hypothalamus (PVN) were shown to contain the melanocortin-4 receptor (MC4R), concentrated in the ventromedial part of the parvicellular PVN (up to 33%). Intracerebroventricular injection of melanocortin agonist MTII to conscious and freely moving rats induced a rapid induction of CRH gene transcription in the PVN. This effect was accompanied by a rise in plasma corticosterone levels in a dose- and time-dependent manner, with the maximum response observed 30 min after MTII injection. MTII (0.5 nmol)-induced increase in plasma corticosterone was attenuated by the selective MC4R antagonist HS014 (0.25-1.0 nmol) and nonselective CRH receptor antagonist alpha-helical-CRH9-41 (0.125-0.5 nmol) in a dose-dependent manner. Moreover, the anorectic effect of MTII was evaluated at 1, 2, and 24 hr after intracerebroventricular injection. Approximately half of the inhibitory effect of MTII (0.5 nmol) on food intake was reversed by pretreatment with alpha-helical-CRH9-41 at 0.25 and 0.5 nmol doses. Collectively, these results provide evidence that CRH acts as a downstream mediator of melanocortin signaling and contributes to the mechanisms by which the central melanocortin system controls feeding and neuroendocrine responses.