Neuropeptide circuitries regulating food and water intake

University dissertation from Stockholm : Karolinska Institutet, Department of Neuroscience

Abstract: An adequate supply of nutrients through food intake is critical for survival, as evidenced by disorders such as obesity and anorexia, which in the long run may be lifethreatening. Feeding behaviour is ultimately controlled by interacting neuronal populations in the brain. The aim of this thesis was to investigate, mainly by histochemical methods, the neuronal pathways involved in this regulation. -Firstly, we investigated the down-stream targets of neuropeptide Y (NPY)-expressing neurones in the hypothalamic arcuate nucleus, which appears to function as a critical center for receiving hormonal information of the metabolic state of the body and initiating food intake. By using as a marker agouti-generelated protein (AGRP), which is solely expressed in the NPY neurones, the projections of this cell group were shown to innervate several nuclei extending from the olfactory nuclei to the nucleus tractus solitarii. Some of the hypothalamic target neurones of this projection were defined histochemically, and found to include neurones expressing cocaine- and amphetamine-regulate transcript (CART) in several nuclei, neurones expressing melaninconcentrating hormone or orexin/hypocretin in the lateral hypothalamic area, neurones expressing thyrotropin-releasing hormone in the paraventricular nucleus and neurones expressing pro-opiomelanocortin (POMC) in the arcuate nucleus. In the latter two populations, we also detected the expression of the NPY Y1 receptor, suggesting that NPY acts partly by inhibiting the activity of anorexigenic peptides. -Secondly, in the mutant anorexia (anx/anx) mouse, which is characterized by decreased food intake, emaciation and premature death, we observed histochemical alterations in both the NPY and POMC arcuate cell populations. In the former, the levels of AGRP- and NPY-like immunoreactivites (-Lls) was increased in the cell bodies and decreased in terminals, whereas no change was observed in the respective mRNA levels; a pattern suggestive of accumulation. In contrast, markers of POMC neurones were decreased in both their peptide and mRNA forms, and stained in a pattern resembling degeneration/ atrophy. These results indicate that a disturbed NPY-POMC circuitry may underlie part of the anx/anx phenotype. -Thirdly, the histochemistry of the nodose ganglion was explored. This ganglion houses the cell bodies of the afferent neurones of the vagus nerve that transmit sensory information from the gastrointestinal tract to the brain, where it may influence food intake on a meal-to-meal basis. Half of the nerve cell bodies in this ganglion expressed CART, and CART peptide-LI could also be detected in the vagus nerve itself and in its central innervation region. In many of the CART neurones, mRNA for the cholecystokinin (CCK)A receptor, which has been implicated as a mediator of satiety, could be detected. These data indicate the existence of a CCK-CART signalling satiety pathway from the gut to the brain. In normal nodose ganglia, expression of CCK and the CCKB receptor was absent/low, but both mRNAs increased dramatically after vagus nerve lesion, suggesting that CCKB receptor signalling may be involved in the neuronal post-traumatic response. Finally, a subpopulation of CCKA receptor-expressing neurones in dorsal root ganglia was also found. -These data contribute to defining the central appetite-regulating circuitries on the basis of neuropeptide content. In particular, the two main input stations in the hypothalamus and the brain stem have been investigated, suggesting a possible convergence of these signals. An understanding of these pathways is likely to be of importance in the development of therapies for eating disorders.

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