Multiple inputs and controls participate in the maintenance of energy homeostasis, and numerous neural and endocrine systems are involved in the integrated responses that maintain energy stores in the body at a level. Since most stored energy is in the form of adipose tissue (fat), and since the brain is the major controller of energy homeostasis, a fundamental requirement is that the brain receive accurate and timely information about the amount and distribution of body fat. This information is then integrated with other factors to determine whether an individual seeks and eats food (i.e., energy intake), as well as the efficiency with which the ingested food is utilized (energy expenditure) or stored. Information regarding the amount of fat stored in the body reaches the brain via the circulating signals insulin and leptin. Each is secreted into the blood in direct proportion to total body fat, and each is transported from the blood into the brain where it interacts with neurons situated to influence energy intake and expenditure. Hence, insulin and leptin are considered to be adiposity signals, and the long-term goal of this project is to elucidate how adiposity signals interact with other factors to influence energy homeostasis. We anticipate that the coming decade will see considerable progress in this arena, as well as the translation of the new-found information into potential novel therapeutic strategies to tackle clinical problems of dysregulation of energy homeostasis (i.e., obesity, eating disorders). With this as an ultimate end point, the present proposal has three specific aims that address critical and as yet unanswered questions regarding the actions of adiposity signals in the brain. The first assesses the hypothesis that insulin and leptin act in the hypothalamus by enhancing the signal provided by local levels of nutrients, including glucose and fatty acids. The second assesses several hypotheses following from our observation that there are important gender differences in the actions of insulin and leptin in the central control of energy homeostasis, and that males and females utilize different strategies to regulate energy homeostasis and defend their body fat stores.
The final aim assesses hypotheses regarding the effect of reducing insulin signaling in specific brain regions on food intake and body weight, and upon related levels of metabolic hormones and neuropeptides, utilizing lentiviral technology.
Hormones such as insulin and leptin that are secreted in direct proportion to body fat interact in the brain with nutrients such as glucose, fatty acids and amino acids to determine food intake and energy expenditure. Proposed research will determine how these signals interact within neurons in the hypothalamus and intervene by manipulating the ability of the brain of laboratory rats to detect and respond to insulin or leptin. Experiments will assess behavior as well as molecular signals within cells.
|Shen, Ling; Wang, David Q H; Xu, Meifeng et al. (2017) BDNF/TrkB signaling mediates the anorectic action of estradiol in the nucleus tractus solitarius. Oncotarget 8:84028-84038|
|Fischer, Katrin; Ruiz, Henry H; Jhun, Kevin et al. (2017) Alternatively activated macrophages do not synthesize catecholamines or contribute to adipose tissue adaptive thermogenesis. Nat Med 23:623-630|
|May, Aaron A; Liu, Min; Woods, Stephen C et al. (2016) CCK increases the transport of insulin into the brain. Physiol Behav 165:392-7|
|May, Aaron A; Bedel, Nicholas D; Shen, Ling et al. (2016) Estrogen and insulin transport through the blood-brain barrier. Physiol Behav 163:312-321|
|Begg, Denovan P; May, Aaron A; Mul, Joram D et al. (2015) Insulin Detemir Is Transported From Blood to Cerebrospinal Fluid and Has Prolonged Central Anorectic Action Relative to NPH Insulin. Diabetes 64:2457-66|
|Wang, Fei; Yang, Qing; Huesman, Sarah et al. (2015) The role of apolipoprotein A-IV in regulating glucagon-like peptide-1 secretion. Am J Physiol Gastrointest Liver Physiol 309:G680-7|
|Mc Allister, Eugenia; Pacheco-Lopez, Gustavo; Woods, Stephen C et al. (2015) Inconsistencies in the hypophagic action of intracerebroventricular insulin in mice. Physiol Behav 151:623-8|
|Grillo, Claudia A; Piroli, Gerardo G; Lawrence, Robert C et al. (2015) Hippocampal Insulin Resistance Impairs Spatial Learning and Synaptic Plasticity. Diabetes 64:3927-36|
|Chambers, Adam P; Smith, Eric P; Begg, Denovan P et al. (2014) Regulation of gastric emptying rate and its role in nutrient-induced GLP-1 secretion in rats after vertical sleeve gastrectomy. Am J Physiol Endocrinol Metab 306:E424-32|
|Lo, Chunmin C; Davidson, W Sean; Hibbard, Stephanie K et al. (2014) Intraperitoneal CCK and fourth-intraventricular Apo AIV require both peripheral and NTS CCK1R to reduce food intake in male rats. Endocrinology 155:1700-7|
Showing the most recent 10 out of 224 publications