The expression of functional receptors for nerve growth factor in insulin-producing cell lines grown in vitro has recently been demonstrated. The possible importance of signals transduced via these receptors in the control of islet maturation has been proposed based on data obtained using an in vitro culture system. To further support this hypothesis, we have studied the expression of Trk-A, the high-affinity receptor for NGF, in vivo during the embryonic and fetal development of the rat pancreas. We have also examined the expression of NGF during the same period. Immunohistological analysis shows that at embryonic day 11 (E11), Trk-A is expressed by the epithelial cells of the presumptive pancreas. The few pancreatic endocrine cells present at that stage express Trk-A. At E12 and E16, Trk-A expression was detected in the developing ductal network. The endocrine cells located in the ducts express Trk-A while those that have migrated into the surrounding mesenchyme now stain negative for Trk-A. By E20, Trk-A expression by ductal cells has considerably decreased and can be detected only in small ducts closely associated with islet-like structures. These islet-like structures stain negative for Trk-A. After birth, insulin-positive cells arranged into islets re-express Trk-A. During the same period, NGF mRNA is found to be expressed in the developing pancreas. The expression of Trk-A and its ligand NGF in the pancreas during embryonic and fetal life suggests that NGF and its receptor could play an important role in the development of the pancreas.

Maternal caloric restriction during late gestation reduces birth weight, but whether long-term adverse metabolic outcomes of intra-uterine growth retardation (IUGR) are dependent on either accelerated postnatal growth or exposure to an obesogenic environment after weaning is not established. We induced IUGR in twin-pregnant sheep using a 40% maternal caloric restriction commencing from 110 days of gestation until term (∼147 days), compared with mothers fed to 100% of requirements. Offspring were reared either as singletons to accelerate postnatal growth or as twins to achieve standard growth. To promote an adverse phenotype in young adulthood, after weaning, offspring were reared under a low-activity obesogenic environment with the exception of a subgroup of IUGR offspring, reared as twins, maintained in a standard activity environment. We assessed glucose tolerance together with leptin and cortisol responses to feeding in young adulthood when the hypothalamus was sampled for assessment of genes regulating appetite control, energy and endocrine sensitivity. Caloric restriction reduced maternal plasma glucose, raised non-esterified fatty acids, and changed the metabolomic profile, but had no effect on insulin, leptin, or cortisol. IUGR offspring whose postnatal growth was enhanced and were obese showed insulin and leptin resistance plus raised cortisol. This was accompanied by increased hypothalamic gene expression for energy and glucocorticoid sensitivity. These long-term adaptations were reduced but not normalized in IUGR offspring whose postnatal growth was not accelerated and remained lean in a standard post-weaning environment. IUGR results in an adverse metabolic phenotype, especially when postnatal growth is enhanced and offspring progress to juvenile-onset obesity.

The growth hormone secretagogue receptor (GHSR) mediates key properties of the gut hormone ghrelin on metabolism and behavior. Nevertheless, most recent observations also support that the GHSR is a constitutively active G protein-coupled receptor (GPCR) endowed with a sophisticated tuning involving a balance of endogenous ligands. Demonstrating the feasibility of shifting GHSR canonical signaling in vivo, we previously reported that a model with enhanced sensitivity to ghrelin (Ghsr ^Q343X mutant rats) developed fat accumulation and glucose intolerance. Herein, we investigated the contribution of energy homeostasis to the onset of this phenotype, as well as behavioral responses to feeding or pharmacological challenges, by comparing Ghsr ^M/M rats to WT littermate rats: (1) as freely behaving animals and (2) in feeding and locomotor paradigms. Herein, Ghsr ^M/M rats showed enhanced locomotor response to a GHSR agonist while locomotor or anorexigenic responses to amphetamine or cabergoline (dopamine receptor 2 agonist), respectively, were preserved. Ad libitum fedGhsr ^M/M rats consumed and conditioned for sucrose similarly to littermate control rats . In calorie-restricted conditions, Ghsr ^M/M rats retained food anticipatory activity and maintained better body weight and glycemia. Importantly, prior to fat accumulation, male Ghsr ^M/M rats preferentially used carbohydrates as fuel substrate without alterations of energy intake, energy expenditure or physical activity and showed alterations of the GHSR system (i.e. enhanced ratio of GHSR hormones LEAP2: acyl-ghrelin and increased Ghsr expression in the hypothalamus). Overall, the present study provides proof for the concept that shifted GHSR signaling can specifically alter nutrient partitioning resulting in modified balance of carbohydrate/lipid utilization.