Control Of Body Energy Homeostasis Research Articles

Neuronal control of energy homeostasis

Neuronal control of body energy homeostasis is the key mechanism by which animals and humans regulate their long-term energy balance. Various hypothalamic neuronal circuits (which include the hypothalamic melanocortin, midbrain dopamine reward and caudal brainstem autonomic feeding systems) control energy intake and expenditure to maintain body weight within a narrow range for long periods of a life span. Numerous peripheral metabolic hormones and nutrients target these structures providing feedback signals that modify the default “settings” of neuronal activity to accomplish this balance. A number of molecular genetic tools for manipulating individual components of brain energy homeostatic machineries, in combination with anatomical, electrophysiological, pharmacological and behavioral techniques, have been developed, which provide a means for elucidating the complex molecular and cellular mechanisms of feeding behavior and metabolism. This review will highlight some of these advancements and focus on the neuronal circuitries of energy homeostasis.

The Long Form of the Leptin Receptor Regulates STAT5 and Ribosomal Protein S6 via Alternate Mechanisms

The action of leptin via the long form of its receptor (LepRb) is central to the control of body energy homeostasis and neuroendocrine function, but the mechanisms by which LepRb regulates intracellular signaling have remained incompletely understood. Here we demonstrate that leptin stimulates the phosphorylation of STAT5 and ribosomal protein S6 in the hypothalamic arcuate nucleus in mice. In cultured cells, we investigate the mechanisms by which leptin regulates each of these pathways. Our analysis reveals a dominant role for LepRb Tyr(1077) (which we demonstrate to be phosphorylated during receptor activation) and a secondary role for LepRb Tyr(1138) in the acute phosphorylation of STAT5a and STAT5b. Tyr(1138) and STAT3 attenuate STAT5-dependent transcription over the long-term, however. In contrast, Tyr(985) (the LepRb phosphorylation site required for ERK activation) mediates the phosphorylation of the ribosomal S6 kinase (RSK) and S6, as well as cap-dependent translation. Thus, these data demonstrate the phosphorylation of Tyr(1077) on LepRb during receptor activation, substantiate the hypothalamic regulation of STAT5 and S6 by leptin, and define the alternate LepRb signaling pathways that mediate each of these signals and their effects in cultured cells. Dissecting the contributions of these individual pathways to leptin action will be important for our ultimate understanding of the processes that regulate energy balance in vivo.

Effects of lactate on glucose-sensing neurons in the solitary tract nucleus

For nervous tissue, lactate is a valuable energy substrate that can be extracted from glucose by astrocytes and released for neuronal use. Therefore, we hypothesized that the glucose-sensing neurons that signal the glycemic changes involved in the control of body energy homeostasis may be responsive to extracellular lactate as well. To test this hypothesis, neuronal activity was recorded extracellularly in the solitary tract nucleus of anesthetized rats in order to compare the effects of microelectrophoretic applications of glucose and lactate and of moderate hyperglycemia and to assess the possible effects of lactate on the response to glucose. About 90% of the investigated neurons behaved in a similar manner after local ejections of glucose and lactate. Among them, most neurons activated by glucose were also activated by lactate and all neurons depressed by glucose were also depressed by lactate. This result suggests that the response to these two compounds is mediated by a common mechanism related to their utilization as oxidizible substrates. In half of the tested neurons, the response to glucose was eliminated or significantly reduced after repeated lactate ejections. This inhibitory effect is a likely result of a modification in glucose metabolism induced by a high extracellular lactate level. Most glycemia-sensitive neurons responded similarly to moderate hyperglycemia and to local lactate ejection, suggesting that high brain lactate levels might interfere with the brain mechanisms that mediate glucoprivic eating.

Insulin and glucose administration stimulates Fos expression in neurones of the paraventricular nucleus that project to autonomic preganglionic structures.

Insulin and glucose play a key role in the control of body energy homeostasis. However, the anatomical organization of the network of central insulin and glucose sensitive areas is still unclear. In the present study, we used a multiple-labelling technique combining retrograde tracing and Fos-like immunohistochemistry, to analyse the anatomical projections from hypothalamic neurones activated by the combined stimulus of insulin and glucose. After intraperitoneal injections of a bolus of insulin plus glucose, Fos-like immunoreactive neurones were observed in the paraventricular nucleus (PVN), ventromedial and arcuate nuclei, as well as the lateral hypothalamic area. In addition, neurones projecting to the autonomic preganglionic levels in the brainstem and spinal cord potentially involved in the control of glucose metabolism were identified by injections of fluorochrome tracers. Thus, Fluorogold was injected into the intermediolateral cell column of the lower spinal cord and Fast Blue was injected into the dorsal motor nucleus of the vagus. Perikarya of descending neurones were detected chiefly in the dorsal, medial and lateral parvocellular subnuclei and also in the posterior magnocellular subnucleus of the PVN. In contrast, insulin-glucose activated neurones in the PVN were observed mainly in the medial parvocellular and posterior magnocellular subnuclei. Fluorogold/Fos double-labelled neurones were only observed in the ventral zone of the medial parvocellular subnucleus. These data indicate that, within the PVN, there could be neurones responding to insulin-glucose administration, which are involved in the sympathetic control of the classical regulatory structures of body energy homeostasis, such as the liver and pancreas, and which could play a role in the output of the neuronal circuitry controlling food intake.

Insulin receptors in the pituitary gland: morphological evidence for influence on opioid peptide-synthesizing cells.

Previous investigations have demonstrated that peripheral insulin has a significant influence on brain function and that the interaction of insulin with neuropeptides in neuroendocrine regions may be pivotal for the regulation of body metabolism and energy balance. Since the various levels of interactions are only incompletely known, the focus of the present study has been the adenohypophysis of the rat, in which the presence and localization of insulin receptors and the structurally and functionally closely related insulin-like growth factor-1 (IGF-1) receptor has been investigated by light- and electron-microscopic immunocytochemistry. The two receptors are found on separate subpopulations of secretory cells of the pars distalis with a preponderance of IGF-1 receptors in a postero-lateral portion of large endocrine cells, insulin receptors being more widely dispersed throughout the pars distalis in a population of smaller, irregularly shaped cells. Insulin receptors, but not IGF-1 receptors, are also located in a subpopulation of secretory cells in the intermediate lobe. Phosphotyrosine, a marker for substrates of receptor tyrosine kinases, has been detected in numerous cells throughout the anterior and intermediate lobe, including the cell populations containing insulin or IGF-1 receptors, indicating their ability to transduce biological signals in the pituitary in vivo. Almost 90% of cells containing insulin receptors are also immunoreactive for beta-endorphin. In contrast, IGF-1 receptors are almost exclusively located on cells secreting follicle-stimulating hormone, suggesting a regulatory role of IGF-1 in the pituitary gonadotropin system. The relationship between beta-endorphin and insulin receptors provides further evidence for the hypothesis that peripheral insulin acts as a regulatory hormone in the control of body energy homeostasis via various steps of the neuroendocrine axis, including opioid peptides in the hypothalamus and pituitary known to play an important role in the regulation of feeding behaviour.