倉科 智行

Aim: Adipocyte lipolysis is mediated by a family of triglyceride (TG) lipases consisting of hormone-sensitive lipase (LIPE), adipose triglyceride lipase (PNPLA2) and carboxylesterase 1 (CES1); however, little is known about the relationship between the expression of each gene in different depots and TG lipase activity or obesity Method: We measured both mRNA expression levels of the lipolytic enzymes (LIPE, PNPLA2 and CES1) and TG lipase activities of biopsy samples obtained from subcutaneous, omental and mesenteric adipose tissues of 34 patients who underwent abdominal surgery. The results were correlated with clinical parameters: adiposity measures, parameters for insulin resistance and plasma lipid levels. Results: PNPLA2 mRNA levels were slightly higher in omental fat than subcutaneous fat. Cytosolic TG lipase activities were positively correlated with the mRNA levels of CES1 in subcutaneous fat and mesenteric fat, while they were correlated with those of PNPLA2 in omental fat. The mRNA levels of LIPE were negatively correlated with various measures of adiposity in subcutaneous fat. The mRNA levels of CES1 were positively correlated with various measures of adiposity, particularly those estimated by CT in the three depots; they were also positively correlated with plasma LDL-cholesterol levels in omental fat. In contrast, the mRNA levels of PNPLA2 were not significantly associated with adiposity. Conclusions: The positive correlations of the expression of CES1 with cytosolic TG lipase activities as well as with adiposity suggest that CES1 is involved in lipolysis, thereby contributing to the development of obesity-associated phenotypes. On the other hand, the expression of LIPE is negatively correlated with adiposity. These distinct regulatory patterns of lipolytic genes may underlie the complex phenotypes associated with human obesity.

A recently discovered satiety molecule, nesfatin-1, is localized in neurons of the hypothalamus and brain stem and colocalized with stress-related substances, corticotropin-releasing hormone (CRH), oxytocin, proopiomelanocortin, noradrenaline (NA) and 5-hydroxytryptamine (5-HT). Intracerebroventricular (icv) administration of nesfatin-1 produces fear-related behaviors and potentiates stressor-induced increases in plasma adrenocorticotropic hormone (ACTH) and corticosterone levels in rats. These findings suggest a link between nesfatin-1 and stress. In the present study, we aimed to further clarify the neuronal network by which nesfatin-1 could induce stress responses in rats. Restraint stress induced c-Fos expressions in nesfatin-1-immunoreactive neurons in the paraventricular nucleus (PVN) and supraoptic nucleus (SON) of the hypothalamus, and in the nucleus of solitary tract (NTS), locus coeruleus (LC) and dorsal raphe nucleus (DR) in the brain stem, without altering plasma nesfatin-1 levels. Icv nesfatin-1 induced c-Fos expressions in the PVN, SON, NTS, LC, DR and median raphe nucleus, including PVN-CRH, NTS-NA, LC-NA and DR-5-HT neurons. Nesfatin-1 increased cytosolic Ca(2+) concentration in the CRH-immunoreactive neurons isolated from PVN. Icv nesfatin-1 increased plasma ACTH and corticosterone levels. These results indicate that the central nesfatin-1 system is stimulated by stress and activates CRH, NA and 5-HT neurons and hypothalamic-pituitary-adrenal axis, evoking both central and peripheral stress responses.