There is a fundamental gap in understanding the mechanism(s) by which estrogens potently inhibit food intake and reduce body weight in many species, including humans. This gap represents an important problem because unless it is closed, it is unlikely that estrogenic intermediaries and pathways can be targeted as a means of obesity prevention and treatment in women with impaired estrogen signaling. Compelling evidence suggests that E2 exerts its anorexigenic action through an indirect mechanism;i.e., that E2 increases the strength of other physiological signals that reduce meal size. Apolipoprotein A-IV (apoA-IV), an important satiation factor, is a compelling candidate in this regard. The objective of this proposal is to identify the mechanisms through which E2 stimulates apoA-IV gene expression in the NTS and to determine how this effect becomes impaired in female rats by chronic high-fat diet (HFD) consumption. The central hypothesis is that E2 normally stimulates apoA-IV gene expression in the NTS and that this effect is impaired by chronic consumption of a HFD, leading to increased food intake and the development of dietary obesity. This hypothesis is based on our preliminary data in HFD-induced obese ovariectomized (OVX) rats. The rationale for the proposed research is that once the particular mechanisms as to how E2 stimulates apoA-IV gene expression and how such effect of E2 is altered by chronic consumption of a HFD are understood, the key component(s) of estrogen signaling could be manipulated pharmacologically, leading to innovative targets to the prevention and treatment of dietary obesity in women. Guided by strong preliminary data, we propose testing this hypothesis by pursuing three specific aims. First, to identify estrogen receptor and DNA response elements that mediate E2's effect on apoA-IV gene expression. Second, to determine whether E2's reduced effect on apoA-IV gene expression contributes to the development of dietary obesity, and whether this can be circumvented by administration of apoA-IV. Third, to determine the mechanism of impaired estrogen signaling in HFD-induced obese female rats. The proposed research is innovative because it translates basic research discovery to a pre-clinical model designed to identify novel treatment targets. This approach represents a substantial departure from the status quo, and is expected to result in an efficacious therapy of obesity in women. This application is significant because it is expected to advance the understanding of how estrogens regulate energy homeostasis in normal female rats, and how such effect is impaired when the animals are fed a HF diet. Ultimately, such knowledge will facilitate the development of preventive and therapeutic interventions to address the epidemic of obesity and, consequently, to improve quality of life for many afflicted individuals and to decrease health care costs in the United States.
The objective of this proposal is to identify the mechanism(s) through which estrogens stimulate apoA-IV gene expression in the brain and to determine how this action is impaired in female rats chronically fed a high-fat diet. Thus, the proposed research is relevant to the part of NIH's mission that pertains to developing fundamental knowledge that will facilitate the development of preventive and therapeutic interventions to address the epidemic of obesity in the United States.
|Shen, Ling; Liu, Yin; Tso, Patrick et al. (2018) Silencing steroid receptor coactivator-1 in the nucleus of the solitary tract reduces estrogenic effects on feeding and apolipoprotein A-IV expression. J Biol Chem 293:2091-2101|
|Zhan, Jesse; Weng, Jonathan; Hunt, Brian G et al. (2018) Apolipoprotein A-IV enhances cholecystokinnin secretion. Physiol Behav 188:11-17|
|Liu, Min; Tso, Patrick; Woods, Stephen C (2018) Receptor CD36 links a risk-associated allele to obesity and metabolic disorders. J Biol Chem 293:13349-13350|
|Woods, Stephen C; May-Zhang, Aaron A; Begg, Denovan P (2018) How and why do gastrointestinal peptides influence food intake? Physiol Behav 193:218-222|
|Woods, Stephen C; May, Aaron A; Liu, Min et al. (2017) Using the cerebrospinal fluid to understand ingestive behavior. Physiol Behav 178:172-178|
|Shen, Ling; Lo, Chunmin C; Woollett, Laura A et al. (2017) Apolipoprotein A-IV exerts its anorectic action through a PI3K/Akt signaling pathway in the hypothalamus. Biochem Biophys Res Commun 494:152-157|
|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|
|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|
|Wang, H H; Liu, M; Portincasa, P et al. (2016) Lack of endogenous cholecystokinin promotes cholelithogenesis in mice. Neurogastroenterol Motil 28:364-75|
|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|
Showing the most recent 10 out of 27 publications