The need to feed: Homeostatic and hedonic control of eating

Leptin Receptor Signaling in Midbrain Dopamine Neurons Regulates Feeding

Leptin resistance in diet-induced obese (DIO) mice is characterized by elevated serum leptin and a decreased response to exogenous leptin and is caused by unknown defects in the central nervous system. Leptin normally acts on several brain nuclei, but a detailed description of leptin resistance within individual brain regions has not been reported. We first mapped leptin-responsive cells in brains from DIO mice using phospho-signal transducer and activator of transcription (P-STAT3) immunohistochemistry. After 16 wk of high-fat-diet feeding, leptin-activated P-STAT3 staining within the arcuate nucleus (ARC) was dramatically decreased. In contrast, other hypothalamic and extrahypothalamic nuclei remained leptin sensitive. Reduced leptin-induced P-STAT3 in the ARC could also be detected after 4 wk and as early as 6 d of a high-fat diet. To examine potential mechanisms for leptin-resistant STAT3 activation in the ARC of DIO mice, we measured mRNA levels of candidate signaling molecules in the leptin receptor-STAT3 pathway. We found that the level of suppressor of cytokine signaling 3 (SOCS-3), an inhibitor of leptin signaling, is specifically increased in the ARC of DIO mice. The study suggests that the ARC is selectively leptin resistant in DIO mice and that this may be caused by elevated suppressor of cytokine signaling 3 in this hypothalamic nucleus. Defects in leptin action in the ARC may play a role in the pathogenesis of leptin-resistant obesity.

Region-Specific Leptin Resistance within the Hypothalamus of Diet-Induced Obese Mice

The discovery of leptin in 1994 has led to astonishing advances in understanding the regulation of energy balance in rodents and humans. The demonstration of leptin receptors in hypothalamic regions known to play critical roles in regulating energy intake and body weight has produced considerable excitement in the field. Most attention has focused on the central actions of leptin. The receptor is present in several populations of neurons that express specific appetite-regulating neuropeptides for which both expression and release are regulated by leptin. Recent advances show that central leptin action is not limited to influencing energy balance. Leptin regulates a broad variety of processes and behaviors, such as blood pressure, neuroendocrine axes, bone mass, and immune function. The cloning of leptin receptors also led to parallel studies examining their signaling capacities in mammalian cell lines. The long-form receptor regulates multiple intracellular signaling cascades, including the classic janus activating kinase-signal transducer and activator of transcription (JAK-STAT) pathway, consistent with belonging to the cytokine-receptor superfamily and the phosphoinositol-3 kinase and adenosine monophosphate kinase pathways. Progress has been made in understanding the role of individual signaling pathways in vivo and the mechanisms by which specific neuropeptides are regulated. Regulation of the pro-opiomelanocortin (pomc) and the thyrotropin-releasing hormone (trh) genes by leptin is particularly well understood. Novel players in negative regulation of central leptin receptor signaling have been identified and open the possibility that these may be important in the development of leptin resistance and obesity. While initial focus was on the central effects of leptin, important actions have been discovered in peripheral tissues. These include roles of leptin to directly regulate immune cells, pancreatic beta cells, adipocytes, and muscle cells. Recent elucidation of a new signaling pathway in skeletal muscle affecting fatty acid metabolism has implications for regulation of insulin sensitivity and glucose metabolism. Recent progress in understanding central and peripheral leptin receptor signaling provides potential new targets for anti-obesity and anti-diabetes drug development.

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Leptin Signaling in the Central Nervous System and the Periphery

The hypothalamic arcuate nucleus: A key site for mediating leptin’s effects on glucose homeostasis and locomotor activity

Leptin is a circulating molecule for the regulation of food intake and body weight suggested to be mediated in the hypothalamus via Ob-Rb receptor, which activates Janus kinase-signal transducer and activator of transcription (STAT) pathways. Although leptin receptors exist in many regions of the brain, there have been few in vivo functional studies of leptin’s target site other than the hypothalamus. We report here that peripherally applied leptin increased STAT3 phosphorylation not only in the hypothalamus but also in the brain stem as assessed by Western blotting. Moreover, administration of leptin induced expression of the suppressor of cytokine signaling 3 mRNA, a negative feedback regulator of leptin signaling, in the brain stem as well as in the hypothalamus. Using immunohistochemistry, we observed phosphorylated STAT3-immunoreactive cells in the arcuate nucleus, ventromedial hypothalamus, lateral hypothalamic area of the hypothalamus, and the nucleus of the tractus solitarius, dorsal motor nucleus...

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Brain stem is a direct target for leptin's action in the central nervous system.

Bacterial endotoxin induces STAT3 activation in the mouse brain

Doping is one of the most serious problems for athletes, and it is important that pharmacists have more interaction with athletes to ensure safer drug usage. Education is one of the most important roles of sports pharmacists, who are specialists regarding drug usage for athletes. We investigated pharmacy students' interests and comprehension regarding drug usage, doping and supplement intake by using the form of a questionnaire, since it is important to know how they understand these subjects as part of their greater educational program. The subjects were sophomore and junior pharmacy students at three universities. It was revealed that most of the students have negative images regarding doping violation, and they answered that they are familiar with doping. However, only sixteen percent of the students had attended lectures by specialists on doping. In addition, one third of pharmacy students did not know that some over-the-counter (OTC) drugs might contain doping substances. With regard to supplement intake, approximately two thirds of the respondents had an interest in and positive image of supplement intake. However, it was revealed that only one third of them recognized supplements as food, and their information regarding supplements was obtained from uncertain media. It was suggested that it is important for pharmacy students to have more opportunities to learn about what doping is. More education and enlightenment by sports pharmacists would be effective for pharmacy students as well as athletes, and it would help us to broaden the scope of what we can do for athletes and society.

Survey on the Attitudes of Pharmacy Students in Japan toward Doping and Supplement Intake

The results of cancer chemotherapy have been improved remarkably by the development of new drugs and combining drugs in treatment. However, cancer chemotherapy protocols are complicated and the adverse effects are more severe than those of other pharmacotherapies. It was therefore felt important to create a database of protocols for the preparation and dispensing of drugs used in cancer chemotherapy.Using Microsoft Access, we have created a database from 320 protocols we have collected so far from 12 clinical departments and developed operating programs for it. The database has enabled us to search for a protocol using keywords-names of drugs, diseases and clinical departments-and most of the operations can be carried out by the click of a mouse. With our database, pharmacists are able to access protocols quickly and check prescriptions of anticancer drugs even if they are unfamiliar with computers, and we consider it to be a useful tool for this purpose.

Toru Kawagishi

Papers

Brain stem is a direct target for leptin's action in the central nervous system.

Bacterial endotoxin induces STAT3 activation in the mouse brain

Survey on the Attitudes of Pharmacy Students in Japan toward Doping and Supplement Intake

Creation of Database of Protocols for Dispensing and Preparation of Cancer Drugs and its Application