Neural control of white, beige and brown adipocytes.

Reports of brown-like adipocytes in traditionally white adipose tissue (WAT) depots occurred ~30 years ago, but interest in white adipocyte 'browning' only has gained attention more recently. We integrate some of what is known about the sympathetic nervous system (SNS) innervation of WAT and brown adipose tissue (BAT) with the few studies focusing on the sympathetic innervation of the so-called 'brite' or 'beige' adipocytes that appear when WAT sympathetic drive increases (for example, cold exposure and food deprivation). Only one brain site, the dorsomedial hypothalamic nucleus (DMH), selectively browns some (inguinal WAT (IWAT) and dorsomedial subcutaneous WAT), but not all WAT depots and only when DMH neuropeptide Y gene expression is knocked down, a browning effect is mediated by WAT SNS innervation. Other studies show that WAT sympathetic fiber density is correlated with the number of brown-like adipocytes (multilocular lipid droplets, uncoupling protein-1 immunoreactivity) at both warm and cold ambient temperatures. WAT and BAT have sensory innervation, the latter important for acute BAT cold-induced temperature increases, therefore suggesting the possible importance of sensory neural feedback from brite/beige cells for heat production. Only one report shows browned WAT capable of producing heat in vivo. Collectively, increases in WAT sympathetic drive and the phenotype of these stimulated adipocytes seems critical for the production of new and/or transdifferentiation of white to brite/beige adipocytes. Selective harnessing of WAT SNS drive to produce browning or selective browning independent of the SNS to counter increases in adiposity by increasing expenditure appears to be extremely challenging.

Changes in microglial activation within the hindbrain, nodose ganglia, and the spinal cord following subdiaphragmatic vagotomy.

Damage to peripheral nerve branches triggers activation of microglia in CNS areas containing motor neuron soma and primary afferent terminals of the damaged fibers. Furthermore, microglial activation occurs in areas containing the soma and terminals of spared nerve branches of a damaged nerve. Because the abdominal viscera are innervated by spinal afferents as well as vagal afferents and efferents, we speculated that spinal nerves might respond like spared nerve branches following damage to vagal fibers. Therefore, we tested the hypothesis that damage to the abdominal vagus would result in microglial activation in vagal structures-the nucleus of the solitary tract (NTS), dorsal motor nucleus of the vagus nerve (DMV), and nodose ganglia (NG)-as well as spinal cord (SC) segments that innervate the abdominal viscera. To test this hypothesis, rats underwent subdiaphragmatic vagotomy or sham surgery and were treated with saline or the microglial inhibitor, minocycline. Microglial activation was determined by quantifying changes in the intensity of fluorescent staining with a primary antibody against ionizing calcium adapter binding molecule 1 (Iba1). We found that subdiaphragmatic vagotomy significantly activated microglia in the NTS, DMV, and NG two weeks post-vagotomy. Microglial activation remained significantly increased in the NG and DMV for at least 42 days. Surprisingly, vagotomy significantly decreased microglial activation in the SC. Minocycline treatment attenuated microglial activation in all studied areas. Our results indicate that microglial activation in vagal structures following abdominal vagal damage is accompanied by suppression of microglial activation in associated areas of the spinal cord.

The arcuate NPY, POMC, and CART expressions responding to food deprivation are exaggerated in young female rats that experienced neonatal maternal separation.

This study was conducted to examine the effect of neonatal maternal separation on the hypothalamic feeding peptides expression in young female offspring. Sprague-Dawley pups were separated from dam for 3h daily during PND 1-14 (MS), or left undisturbed except routine cage cleaning (NH). Weanling female pups were housed in group and the arcuate mRNA levels of neuropeptide Y (NPY), proopiomelanocortin (POMC), and cocaine-amphetamine regulated transcript (CART) were examined at two months of age with or without food deprivation. The basal arcuate expression levels of these peptides did not differ between NH and MS group. However, a 48 h of food deprivation significantly increased NPY mRNA level, and decreased POMC and CART, in the arcuate nucleus of MS females, but not in NH females. Fasting-induced elevation of the plasma corticosterone tended to be greater in MS group than in NH, but the basal levels did not differ between the groups. Plasma leptin levels were decreased in MS females compared with NH, and food deprivation significantly suppressed the leptin levels both in NH and MS groups. Results suggest that MS experience may increase stress vulnerability in female rats and exaggerate the feeding peptides expression in the arcuate nucleus responding to metabolic stress food deprivation.

Mesolimbic dopaminergic activity responding to acute stress is blunted in adolescent rats that experienced neonatal maternal separation.

Neonatal maternal separation (MS), stressful experience early in life, leads to the development of depression-like behaviors in the offspring later in life. This study was conducted to define the neural basis of depression-like behaviors observed in our MS model. Sprague-Dawley pups were separated from dam for 3 h daily during the first 2 weeks of birth (MS) or left undisturbed (NH). All pups were sacrificed on postnatal day 41 with/without 1 h of restraint stress. Restraint stress significantly increased c-Fos expression in the nucleus accumbens (NAcb) of NH pups, but not in MS. In NH pups, restraint stress increased dopamine levels not only in the NAcb but also in the midbrain dopamine neurons; however, these increases were not observed in MS. Gene expression of tyrosine hydroxylase (TH) in the ventral tegmental area (VTA) was increased by acute restraint in NH pups, but not in MS pups. The raphe serotonin level was lower in MS than in NH, and not significantly changed by acute restraint neither in NH nor in MS. Results reveal that experience of neonatal MS may lead to a long-term suppression in the mesolimbic dopamine system of the offspring later in life, in which an epigenetic control may be implicated, such as suppressed gene expression of TH in the midbrain. We conclude that a decreased activity of the mesolimbic dopamine system may play a role in the pathophysiology of depression-like behaviors by neonatal MS, in addition to a decreased serotonin level in the raphe nucleus.

Plasticity of nodose ganglion neurons after capsaicin- and vagotomy-induced nerve damage in adult rats.

Previous reports show that vagal afferent innervation of the stomach eventually regenerates from surviving nodose ganglion (NG) neurons after subdiaphragmatic vagotomy. Systemic capsaicin treatment destroys gastric vagal afferent neurons expressing vanilloid receptor 1 (VR1). However, it is not known whether gastric innervation lost after neuronal destruction can be restored. Here, we report that capsaicin-induced damage of NG neurons innervating the stomach in adult rats is followed by restoration of vagal afferent projections. Specifically, we compared measures of neuronal plasticity in NG and vagi after subdiaphragmatic vagotomy or capsaicin treatment. The numbers of VR1-immunoreactive neurons projecting to the stomach were significantly reduced 10 days after either capsaicin treatment or vagotomy. However, the VR1-immunoreactive afferent innervation of the stomach was restored to levels exceeding those of vagotomized rats by 37 days after capsaicin, whereas neither total afferent innervation nor VR1-immunoreactive innervation reached control levels, even by 67 days after vagotomy. Capsaicin treatment significantly increased NG neuronal nitric oxide synthase (nNOS) immunoreactivity at 10 days after capsaicin, and this increase was sustained for the duration of the study, indicating higher nNOS demand in restoration of vagal projections. Vagotomy was associated with a much smaller increase in the number of nNOS-immunoreactive NG neurons, detectable only at 10 days after surgery. The number of nNOS-immunopositive gastric-projecting neurons was dramatically reduced 10 days after either capsaicin treatment or vagotomy but returned to the control level in both groups at 67 days. We found a significantly higher number of growth cones in capsaicin-treated animals compared with controls. Capsaicin significantly increased the number of nNOS-immunopositive and nNOS-immunonegative growth cones in NG at all time points. Vagotomy did not increase the number of nNOS(-) growth cones in NG. We conclude that capsaicin treatment may result in more significant restorative capacities than vagotomy, mainly because of sprouting of capsaicin-insensitive nerve fibers.

Sustained hyperphagia in adolescent rats that experienced neonatal maternal separation.

OBJECTIVE: To examine the neurobiological basis of bingeing-related eating disorders using an animal model system. DESIGN: Sprague-Dawley pups were separated from dam for 3 h daily during the first two weeks of birth (maternal separation (MS)), or left undisturbed (non-handled (NH)). Pups were subjected to repeated fasting/refeeding (RF) cycles; that is, 24 h food deprivation and 24 h RF (NH/RF or MS/RF), or had free access to food and water (NH/fed control (FC) or MS/FC) from postnatal day (PND) 28-40. MEASUREMENTS: Body weight gain and food intake were recorded. The arcuate expression of neuropeptide Y (NPY) and plasma corticosterone levels were analyzed on PND 29 and 40. RESULTS: Decrease in weight gain by repeated fasting/RF cycles was smaller in MS pups than in NH. Interestingly, weight changes responding to fasting or RF increased in MS/RF compared with NH/RF. Compensatory hyperphagia was diminished in NH/RF after the third fasting trial, but persisted in MS/RF throughout the experimental period. The arcuate expression of NPY mRNA responding to food deprivation was blunted, but elevation of plasma corticosterone exaggerated, in the MS group, compared to the NH group, on PND 29 after the first fasting session. However, both the arcuate NPY mRNA and plasma corticosterone levels were increased in MS/RF, but not in NH/RF, on PND 40 after the six sets of fasting/RF cycles, compared to the free FC groups. CONCLUSION: Experience of neonatal MS may lead to an exaggerated feeding response to repeated fasting/RF challenges at adolescence, perhaps, due to increased responsiveness of the hypothalamic-pituitary-adrenal gland axis. Additionally, the results suggested that an increased action of the hypothalamic NPY may not be necessary to induce compensatory hyperphagia following food deprivation.