Nutrient-sensing mechanisms in hypothalamic cell models: neuropeptide regulation and neuroinflammation in male- and female-derived cell lines.

The hypothalamus is responsible for the control of many of our physiological responses, including energy homeostasis. Of interest, there are a number of instances of sexual dimorphism documented with regard to metabolic processes. This review will discuss the necessity of utilizing both male and female models when studying the mechanisms underlying energy homeostasis, particularly those originating at the level of the hypothalamus. Because obesity often results in central neuroinflammation, we describe markers that could be used to study differences between male and female models, both the whole organism and also at the cellular level. Our laboratory has generated a wide array of immortalized hypothalamic cell models, originating from male and female rodents that we suggest could be beneficial for these types of studies. It is imperative that both sexes are considered before any recommendations for therapeutic interventions are considered.

Neonatal immune challenge affects the regulation of estrus cyclicity and feeding behavior in female rats.

A single immune challenge with lipopolysaccharide (LPS) in the neonatal period has a long-lasting influence on immune response. Using female Sprague-Dawley rats, we examined whether neonatal LPS challenge influences the life-long neuroendocrine sensitivity of reproductive function and feeding behavior to LPS, and whether stress-related neuropeptides and their receptors are involved in neonatal LPS-induced physiological change. On day 10 after birth, all pups were injected with LPS (100 microg/kg, i.p.) or saline. Then, in Experiment 1, LPS (100 microg/kg, i.p.) or saline was injected at diestrous in adulthood, and the length of the estrous cycle, 24h food intake and body weight change were recorded. In Experiment 2, the mRNA expression levels of corticotropin-releasing hormone (CRH), urocortin (UCN), urocortin 2 (UCN2), CRH receptor type 1 (CRH-R1) and CRH receptor type 2 (CRH-R2) in the hypothalamus were measured using real-time PCR. LPS injection in adulthood prolonged the estrous cycle in neonatal LPS-injected rats. LPS injection in adulthood decreased food intake and body weight in both neonatal LPS- and saline-injected rats, more so in the latter. Basal expressions of UCN2 and CRH-R2 mRNA were higher in neonatal LPS-injected rats than in saline-injected rats. These findings indicate that neonatal immune challenge influences the anti-stress regulation of the estrous cycle and feeding behavior in adulthood. Increased expression of UCN2 and CRH-R2 might enhance the sensitivity of the estrous cycle in suppressing the effects of LPS.

Active immunization against ghrelin decreases weight gain and alters plasma concentrations of growth hormone in growing pigs.

Ghrelin has been implicated in the control of food intake and in the long-term regulation of body weight. We theorize that preventing the ability of ghrelin to interact with its receptors, would eventually lead to decreased appetite and thereby decrease body weight gain. To test our hypothesis, pigs were actively immunized against ghrelin. Ghrelin((1-10)) was conjugated to BSA and emulsified in Freund's incomplete adjuvant and diethylaminoethyl-dextran. Primary immunization was given at 19 weeks of age (WOA), with booster immunizations given 20 and 40 days after primary immunization. Body weight (BW) and plasma samples were collected weekly beginning at 19 WOA, and feed intake was measured daily. Fourteen days after primary immunization, the percentage of bound (125)I-ghrelin in plasma from immunized pigs was increased compared with control animals (P<0.001). Voluntary feed intake was decreased more than 15% in animals that were actively immunized against ghrelin compared with controls. By the end of the experiment, immunized pigs weighed 10% less than control animals (P<0.1). Concentrations of GH were increased (P<0.05) in immunized pigs. Apoptosis was not observed in post-mortem samples obtained from the fundic region of the stomach. Our observations suggest that immunization against ghrelin induces mild anorexia. This procedure could potentially be used as a treatment to control caloric intake and obesity.