Afferent inputs to the brain with relevance for energy homeostasis include external (visual, olfactory, auditory, tactile) as well as internal stimuli generated by food after its ingestion (pregastric, gastric, postgastric) and postabsorptive stimuli such as those generated by mucosal nutrient transport mechanisms and the associated release of local hormones (e.g. CCK) acting through the circulation or on visceral sensory nerves. Other postabsorptive signals are nutrients, metabolites and hormones acting on sensors in the portal hepatic space (e.g. glucose) or directly on hepatic sensors (e.g. glucagon), as well as metabolites, hormones and other factors originating from various tissues, circulating in the blood or lymph and activating corresponding sensors directly in the brain (glucose, amino acids and leptin). Another way of differentiating afferent signals refers to their abilities to induce a positive or negative energy balance.
The gastrointestinal hormone ghrelin for example induces a positive energy balance, while numerous other peripheral hormones such as cholecystokinin (CCK)are known to promote a negative energy balance. Thirdly, insulin should be considered a main coordinator of the crosstalk between periphery and central sensors. Its function as a double-edged sword serves to store nutrient-derived energy as fat and glycogen on the one hand. On the other hand excess insulin, as specifically observed in early type 2 (pre-)diabetes causes hunger both directly as well as via induction of hypoglycemia, which subsequently causes the appropriate neuroendocrine response, i.e. food uptake for elevation of bloodglucose.
Endocrine signals reflecting metabolic state arise from several peripheral organs such as the thyroid, the adrenals, the reproductive tissue, the fat tissue and gastrointestinal organs. Being secreted according to the current status of metabolism and energy homeostasis, these hormones convey information to multiple specific areas in the brain. Among the more relevant of these signals, is the gastrointestinal hormone CCK, which was first discovered in 1973. Peripherally released CCK acts centrally to trigger satiety and to initiate a negative
energy balance via pathways predominantly localized in the brainstem. CCK is thought to have a physiological role in regulating meal termination and has long been mistaken as the crucial missing factor in the ob/ob mouse. The ob/ob mouse phenotype results from a spontaneous mutation, which was speculated long before its identification to be caused by the lack of a peripheral signal informing the brain about existing energy stores. Although the molecular technology was lacking to isolate the responsible gene or its product, brilliant
parabiosis experiments performed by Coleman and coworkers, connecting the circulation of ob/ob mice with that of their genetically normal littermates, yielded the proof of this concept. Positional cloning of the ob gene finally led to the discovery of the proteohormone leptin, which is predominantly produced by adipose cells according to the size of fat stores. Administration of leptin induces a negative energy balance that is mediated by specific neuronal structures in the hypothalamus and the brainstem. Leptin’s role in signaling the brain about chronic changes in energy status is completed by insulin conveying additional information about long-term changes of peripheral metabolism to the brain. Centrally administered insulin causes a negative energy balance, while neuron-specific deletion of its receptor is causing obesity. Along with these signals, which are most likely contributing to chronic energy balance regulation, hormones reflecting caloric intake and acute nutritional requirements complete the information flow to the brain. One of these factors, PYY(3–36), a gastrointestinal hormone which is secreted in response to ingestion of food and is thought to act via hypothalamic Y2 receptors, has recently been reported to acutely induce a negative energy balance response to ingestion of a meal. The only known peripherally secreted orexigenic hormone, the gastro-enteric peptide ghrelin, counterbalances energy homeostasis in opposition and completion to the multiple anorectic signals described above. Ghrelin, which induces a positive energy balance predominantly at the same neuronal structures where leptin and PYY(3 36) exert their action, triggers an increased in fat mass in rodents and at the least stimulates hunger in humans. Since ghrelin is secreted in response to caloric restriction and its expression and secretion are rapidly suppressed by food intake, a physiological role in meal initiation as the endogenous ‘hunger hormone’ has been proposed. A large number of other gastrointestinal hormones and adipokines have been identified as afferent signals being involved in energy balance regulation, but either their exact mechanism of action is not yet understood or their physiological role remains unclear. Intestinal glucagon-like peptide 1 (GLP-1) decreases appetite and food intake in rodents, deletion of receptors for glucose dependant insulinotropic polypeptide (GIP) protects against obesity, while the fat-cell derived interleukin 6 is a cytokine that centrally induces a negative energy balance. The classical endocrine axis, especially the hypothalamic-pituitary-adrenal (HPA), the hypothalamic-pituitary-thyroid (HPT) and the growth hormone/IGF-1 axis, although being largely neglected as afferent signals of acute and chronic energy balance to the brain, certainly also play an important role in the complex networks governing appetite and body weight. Central administration of corticosteroids for example induces appetite and increases fat mass.
energy balance via pathways predominantly localized in the brainstem. CCK is thought to have a physiological role in regulating meal termination and has long been mistaken as the crucial missing factor in the ob/ob mouse. The ob/ob mouse phenotype results from a spontaneous mutation, which was speculated long before its identification to be caused by the lack of a peripheral signal informing the brain about existing energy stores. Although the molecular technology was lacking to isolate the responsible gene or its product, brilliant
parabiosis experiments performed by Coleman and coworkers, connecting the circulation of ob/ob mice with that of their genetically normal littermates, yielded the proof of this concept. Positional cloning of the ob gene finally led to the discovery of the proteohormone leptin, which is predominantly produced by adipose cells according to the size of fat stores. Administration of leptin induces a negative energy balance that is mediated by specific neuronal structures in the hypothalamus and the brainstem. Leptin’s role in signaling the brain about chronic changes in energy status is completed by insulin conveying additional information about long-term changes of peripheral metabolism to the brain. Centrally administered insulin causes a negative energy balance, while neuron-specific deletion of its receptor is causing obesity. Along with these signals, which are most likely contributing to chronic energy balance regulation, hormones reflecting caloric intake and acute nutritional requirements complete the information flow to the brain. One of these factors, PYY(3–36), a gastrointestinal hormone which is secreted in response to ingestion of food and is thought to act via hypothalamic Y2 receptors, has recently been reported to acutely induce a negative energy balance response to ingestion of a meal. The only known peripherally secreted orexigenic hormone, the gastro-enteric peptide ghrelin, counterbalances energy homeostasis in opposition and completion to the multiple anorectic signals described above. Ghrelin, which induces a positive energy balance predominantly at the same neuronal structures where leptin and PYY(3 36) exert their action, triggers an increased in fat mass in rodents and at the least stimulates hunger in humans. Since ghrelin is secreted in response to caloric restriction and its expression and secretion are rapidly suppressed by food intake, a physiological role in meal initiation as the endogenous ‘hunger hormone’ has been proposed. A large number of other gastrointestinal hormones and adipokines have been identified as afferent signals being involved in energy balance regulation, but either their exact mechanism of action is not yet understood or their physiological role remains unclear. Intestinal glucagon-like peptide 1 (GLP-1) decreases appetite and food intake in rodents, deletion of receptors for glucose dependant insulinotropic polypeptide (GIP) protects against obesity, while the fat-cell derived interleukin 6 is a cytokine that centrally induces a negative energy balance. The classical endocrine axis, especially the hypothalamic-pituitary-adrenal (HPA), the hypothalamic-pituitary-thyroid (HPT) and the growth hormone/IGF-1 axis, although being largely neglected as afferent signals of acute and chronic energy balance to the brain, certainly also play an important role in the complex networks governing appetite and body weight. Central administration of corticosteroids for example induces appetite and increases fat mass.
While the negative energy balance induced by thyroid hormones is mainly attributed to their multiple peripheral effects, T4 as well as T3 receptors are also localized in the brain, where they serve as crucial feedback targets and allow for direct modulation or circuits regulating energy balance. Comparable feedback principles exists for hormones of the somatotropic axis such as growth hormone and IGF-1, which represent well established determinants of body composition. Apart from these and other hormones, essential metabolic substrates add to the integrated signal emerging from the periphery: glucose and free fatty acids directly inform centrally located sensors about the current state of carbohydrate and lipid metabolism. But not only endocrine factors and circulating metabolites provide afferent information for central circuits controlling energy balance. Satiety information generated during the course of a meal is largely conveyed to the brainstem by means of afferent fibers of the vagus nerve and by afferents passing from the spinal cord from the upper gastrointestinal tract. This information converges in the nucleus tractus solitarius (NTS) an area in the caudal brainstem that integrates sensory information from the gastrointestinal tract and abdominal viscera, as well as taste information from the oral cavity
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