Catherine M. Kotz - US grants

The lateral hypothalamus (LH) has a historical role as the "feeding center" of the brain. Although energy regulation is now known to be more complex, the role of the LH in food intake and body weight regulation remains strong. The recent discovery of the hypocretins (also known as orexins), Hcrt 1 and Hcrt 2, appears to provide a means to expand understanding of the LH and its role in the energy regulatory network. The Hcrts are newly identified orexigenic neuropeptides that elicit dose-dependent feeding following LH administration, and appear to interact with a variety of other important feeding-regulatory circuits. The Hcrt receptors are widely distributed throughout the brain, and are found in several key energy regulatory sites. Hcrt-containing neurons within the LH project to and activate several of these sites. The finding that LH Hcrt-containing neurons communicate with other key brain sites involved in appetite and body weight regulation, and the finding that Hcrt stimulation of LH activates those sites is, we think, of critical importance. The investigators have experience probing the nature of interactions between brain sites connected by specific neuromodulators. The existing data indicates that such an approach will be very useful in determining how the LH and the Hcrts fit into the energy regulatory network, and will aid in our understanding of energy homeostasis and metabolic disorders. Further, if the neural pathways influenced by the Hcrts are determined, then pharmacological alteration of these pathways can be explored. The overall hypothesis to be tested is as follows: hypocretin containing neural pathways originating in the LH communicate with other feeding regulatory brain sites and neuromodulators in an integrated fashion to modulate feeding. The specific aims of this project are to localize the specific site of Hcrt action within the LH, verify the significance of Hcrt in the LH by testing other regions for Hcrt feeding effects (mapping/feeding studies); measure behaviors and meal patterns elicited in response to LH Hcrt (feeding/behavioral studies); develop the neural map of feeding sensitivity to Hcrt 1 (cFos immunohistochemistry, lesion/feeding studies); determine amino acid involvement in Hcrt 1 induced feeding (GABA)/glutamate interaction feeding studies); and determine communication between LH Hcrt feeding signals and other feeding related neuromodulators (interaction feeding studies).

DESCRIPTION (provided by applicant): Obesity and overweight affects most Americans, but there are some who resist obesity, just as some animals resist obesity. Animal and human studies indicate that spontaneous physical activity (SPA), which generates nonexercise activity thermogenesis (NEAT), is an important defense against weight gain. Brain mechanisms control the level SPA, and the NEAT so generated, but the specifics are undefined. We propose that hypothalamic orexin A (OxA) is an important part of the SPA regulatory pathway, and that sensitivity to OxA signals enhancing SPA and NEAT helps determine propensity for obesity. The objectives of this application are to test the following hypotheses: (1) elevated OxA mediated SPA protects against weight gain and (2) increased OxA-mediated SPA in obesity resistant (OR) rats results from increased orexin receptor expression. Our long-range goal is to use knowledge of SPA and NEAT regulatory pathways to guide therapeutic interventions on these mechanisms among obese humans. We plan 3 aims: Aim 1) Characterize orexin neuron subpopulations important to SPA. A) Are there strain differences in orexin message and peptide in subpopulations of orexin neurons? B) Does destruction of subpopulations of orexin neurons affect SPA? Aim 2) Determine importance of OxA-mediated SPA to weight gain. A) Does reduced OxA action in rLH of OR rats reduce resistance to weight gain? B) Does SPA induced by high dose OxA stimulation of rLH reduce weight gain in OP rats? Aim 3) Verify that increased orexin sensitivity in OR rats is due to increased orexin receptor expression. A) Is orexin receptor number increased in OR compared to OP rats? B) Is c-fos activation in rLH orexin receptor bearing neurons higher in OR than OP rats? C) Does reducing orexin receptor bearing neurons in rLH of OR rats enhance weight gain? A greater understanding of brain orexin and its relationship to SPA in obesity will fill a large gap in knowledge of centrally mediated SPA and NEAT, and its importance to obesity resistance. PUBLIC HEALTH RELEVANCE The current proposal is aimed at understanding the role of a specific brain pathway that controls physical activity, which is important to body weight regulation. Obesity is a major health problem affecting at least one third of the U.S. population, and is a risk factor for several diseases, including heart disease, diabetes and several types of cancer. Underlying part of the problem is disordered regulation of physical activity, and a better understanding of the brain pathways important to this is necessary in developing treatments for obesity.

DESCRIPTION (provided by applicant): Treatments for obesity remain limited and with low success. Current therapies do not account for known differences in individual obesity susceptibility, which might be key for developing successful treatments. Susceptibility and severity to obesity are linked to individual differences in spontaneous physical activity (SPA). Our long-term goal is to provide the biological basis for development of personalized obesity therapies. To do this, we will use a novel model of differential susceptibility to obesity, the hig activity (HA) and low activity (LA) rats. HA rats are obesity resistant and higher signaling by orexin peptides than LA rats. The orexins are key modulators of SPA and energy balance. Our overall goal is to define the mechanisms underlying orexin involvement in to SPA and their relevance to obesity susceptibility in the HA/LA rat model. A long-standing hypothesis about the orexins is their functional specialization, which proposes that orexin neurons in the lateral hypothalamus (LH) mediate reward, while neurons in the perifornical area (PeF) and dorsomedial hypothalamus (DMH) mediate arousal. Aim 1 will determine which orexin neuron subpopulations (LH or PeF/DMH) are more relevant for the HA/LA phenotype. We will knock- down and over-express orexins in these areas to test their necessity or sufficiency for SPA in. Next, we will focus on orexin signaling through rostral LH (rLH). This pathway mediates increases in SPA and may be key for expression of the HA phenotype. Aim 2 will determine the relevance of rLH orexin signaling to obesity susceptibility in HA/LA rats. We will determine how obesity affects orexin rLH signaling in HA/LA rats and if blocking orexin responses in rLH increases obesity susceptibility in HA rats. Next, we will study interactions between rLH and nucleus accumbens shell (NAcSh). NAcSh interacts with orexin neurons to affect feeding and SPA. Inhibition of NAcSh GABAergic efferents increases SPA caused by orexin injection in rLH in LA, but not in HA rats. Aim 3 will study NAcSh and rLH interactions in the HA/LA phenotype. We will determine if there is a combined effect of rLH and NAcSh orexin signaling in HA rats, whether feeding responses after manipulation of NAcSh are different between HA/LA rats and define the neuroanatomical connections between NAcSh and rLH orexin-responsive neurons. These studies will fill the gap in knowledge of orexin neural circuitry in mediating phenotypic differences between HA and LA rats, which will improve our understanding of brain mechanisms underlying individual obesity susceptibility and enhance therapeutic approaches to obesity.

? DESCRIPTION (provided by applicant): Halting and reversing upward secular trends in body weight in the US is an important medical and public health challenge. Additional skilled researchers in obesity prevention are much needed, but training programs are few. Obesity is a complex disorder that has multiple causes and multiple potential strategies for prevention and treatment. The present proposal is a competitive renewal application for a training grant called the Minnesota Obesity Prevention Training (MnOPT) program. Originally funded in 2010, its goal is to provide multidisciplinary training for a new generation of obesity prevention scientists MNOPT has successfully recruited 9 trainees over the last four years from a large pool of highly qualified applicants, six post docs and three predocs, all of whom have been matched with appropriate mentors and all of whom have been productive. We have also conducted a successful educational program with interdisciplinary training for all fellows in biological mechanisms and clinical and public health interventions as well as training in ethical conduct of research. We have directed each of the fellows to educational experiences, e.g. research design and analysis, as individually appropriate. We are proposing only minor changes to this successful program in this renewal. Because of the size and composition of the applicant pool, we are requesting two additional training slots to the five already approved and are also planning to combine the existing basic science and clinical tracks into a single training track. Robert Jeffery will remain the overall director, as well as director of the epidemiology/behavioral track, and Catherine Kotz, professor in the Department of Food Science and Nutrition, will serve as co-director and director of the basic science/clinical track. The research base at the University of Minnesota remains strong. The number of participating faculty has decreased from 36 in the original application to 33 in the current renewal to include only those with documented mentoring experience and the strongest research base. The institutional support for the training program has also strengthened since the initial proposal.