Research Project: Molecular, Cellular, and Regulatory Aspects of Obesity Development

Location: Children's Nutrition Research Center

2024 Annual Report

Objectives
Obesity and its associated metabolic disorders represent a serious health problem to our society. To address this researchers aim to: 1) determine if potassium channels (SK3) expressed by serotonin neurons are required to regulate feeding behavior and body weight balance using a Cre-loxP strategy to generate mouse models that either lack SK3 selectively in serotonin neurons and test if these manipulations in mice alter animals' food intake and body weight; 2) identify downstream neural circuits that mediate serotonin neuron actions to regulate feeding behavior and body weight balance and selectively stimulate specific downstream neural circuits that originate from brain serotonin neurons in mice, and measure effects on animals' feeding behavior and body weight; 3) identify upstream and downstream signaling molecules of glycogen synthase kinase 3 beta that controls suppressor of cytokine signaling 3 levels and cellular insulin and leptin actions in the hypothalamus by using an ex vivo brain slice model; 4) determine if each component of the glycogen synthase kinase 3 beta-related pathway determines hypothalamic levels of suppressor of cytokine signaling 3 and hypothalamic leptin and insulin actions in vivo by using genetically engineered mouse models; 5) determine the physiological roles of genetically defined Agouti-related protein/proopiomelanocortin-parabrachial nucleus circuit in differential control of feeding behavior and energy metabolism; 6) determine the physiological roles of key gamma amino butyric acid and N-methyl-D-aspartic acid glutamate receptor subunits expressed in the Agouti-related protein/proopiomelanocortin-parabrachial nucleus circuit for the regulation of appetite, energy balance, and development of obesity; 7) investigate the interaction of various phospholipid species with the LRH-1 nuclear receptor, and determine the potential metabolic benefits to insulin resistance in obesity; 8) use transgenic mice with liver specific knockout of the liver receptor homolog LRH-1 nuclear receptor to critically test its role as the potential mediator of the metabolic benefits of phosphatidylcholine agonist ligands in obesity; 9) removed due to investigator departure; 10) removed due to investigator departure; 11) determine if maternal obesity and high-fat diet during gestation induce adipogenic and metabolic program alterations in Wt1 expressing white adipocyte progenitor cells during development; 12) assess if carbohydrate response element binding protein alters macrophage intracellular metabolism and inflammatory response; 13) assess if macrophage carbohydrate response element binding protein activity affects adipose tissue inflammation and the development of diet-induced obesity and insulin resistance; and 14) use wild type mice to determine organ specific metabolism of fatty acids of varying carbon chain lengths, and study their effects on the progression and/or treatment of diet-induced obesity and its related metabolic disorders.

Approach
A multi-discipline approach will be undertaken to address these concerns. Rodent models will be utilized to examine the role of small-conductance Ca2+-activated K+ currents in 5-HT neurons in the regulation of hedonic feeding and we will work to identify a previously unrecognized neural signaling pathway that controls leptin and insulin actions in the hypothalamus and mediates whole-body energy balance. Collectively, the studies will demonstrate the potential roles of metabolic cues (hormones/nutrients), central nervous system circuits, and the intra-neuronal signals in the control of energy and glucose homeostasis. Our research results should identify rational targets for the treatment or prevention of obesity and diabetes. Researchers will also study the role of endogenous phosphatidylcholines in the prevention and treatment of non-alcoholic fatty liver disease and insulin resistance, and test the hypothesis that beneficial effects of these natural phosphatidylcholines are due to LRH-1 activation. We will also will use mouse models of diet-induced obesity and will focus on three general problems associated with obesity: the developmental effects of maternal obesity on offspring adiposity, adipose tissue inflammation that may lead to medical complications, and the effects of dietary fatty acid composition on obesity.

Progress Report
To review the progress made during the year, please refer to the following projects: 3092-10700-069-010S (Project #1), 3092-10700-069-020S (Project #2), and 3092-10700-069-050S (Project #3).

Accomplishments
1. A new way to reduce hedonic eating. Eating can be driven by both hunger and by hedonic (pleasant sensations) values of foods. The latter is a contributing factor to obesity. Researchers at the Children's Nutrition Research Center in Houston, Texas, discovered that a certain type of brain cells, called 5-hydroxytryptamine (5-HT) neurons, can suppress hedonic feeding. We revealed how 5-HT cells are regulated by nutrient intake and how these cells send signals to the downstream cells to regulate feeding behaviors. These findings are significant and provide a framework to potentially target these specific cells for the prevention and/or treatment of obesity.

2. Mapping brain responses to food. Aside from internal cues originating from an empty or full stomach, the brain plays a significant role in controlling our drive to eat; whether we find something appealing or disgusting often comes from the sites, smells, or memories of a given dining experience. We are studying the brain circuits that govern non-nutrient based eating actions, whereby sensory input and life experience impacts eating habits. Researchers at the Children's Nutrition Research Center in Houston, Texas, used genetically engineered mice to directly monitor brain activity during both normal and altered feeding behavior. We have learned that the brain circuits that evaluate the value of food are the same as those that are associated with reward and avoidance, and when altered can manifest in unhealthy eating habits that underly addiction and aversion. Our results have helped identify brain areas not previously known to be involved with feeding behavior and may provide new potential therapeutic targets for treating not only eating disorders, but other forms of neuropsychiatric disease.

3. Nutritional input is fundamental to the development and treatment of obesity. A diet consisting of a high intake of fat and sugar can lead to a high prevalence of obesity and its related health complications. Scientists at the Children's Nutrition Research Center in Houston, Texas, recently found the requirement of an essential amino acid (phenylalanine) that is commonly found in high protein foods like meat, beans, milk, and eggs, was necessary for the development of diet-induced obesity. Restriction of phenylalanine protected mice from diet-induced weight gain. These findings are important as it provides evidence that restricting nutritional phenylalanine intake could be exploited as a potential strategy to treat or prevent obesity.

Review Publications
Liang, Y., Pan, C., Yin, T., Wang, L., Gao, X., Wang, E., Quang, H., Huang, D., Tan, L., Xiang, K., Wang, Y., Alexander, P.B., Li, Q., Yao, T., Zhang, Z., Wang, X. 2023. Branched-chain amino acid accumulation fuels the senescence-associated secretory phenotype. Advanced Science. 11(2). Article 2303489. https://doi.org/10.1002/advs.202303489.
Hauck, J., Moon, D., Jiang, X., Wang, M., Zhao, Y., Xu, L., Quang, H., Butler, W., Chen, M., Macias, E., Gao, X., He, Y., Huang, J. 2024. Heat shock factor 1 directly regulates transsulfuration pathway to promote prostate cancer proliferation and survival. Communications Biology. 7. Article 9. https://doi.org/10.1038/s42003-023-05727-9.
Yang, L., Peery, R.C., Farmer, L.M., Gao, X., Zhang, Y., Creighton, C.J., Zhang, L., Shen, L. 2024. Dietary folate and cofactors accelerate age-dependent p16 epimutation to promote intestinal tumorigenesis. Cancer Research Communications. 4(1):164–169. https://doi.org/10.1158/2767-9764.CRC-23-0356.
Moon, D., Hauck, J., Jiang, X., Quang, H., Xu, L., Zhang, F., Gao, X., Wild, R., Everitt, J.I., Macias, E., He, Y., Huang, J. 2023. Targeting glutamine dependence with DRP-104 inhibits proliferation and tumor growth of castration-resistant prostate cancer. Prostate. 84(4):349–357. https://doi.org/10.1002/pros.24654.
Waterstraat, M.G., Wang, Z., Kogiso, M., Caballero-Juarez, R., Chen, M. 2024. Dissection, histological processing, and gene expression analysis of murine supraclavicular brown adipose tissue. The Journal of Visualized Experiments (JoVE). 205. Article e66475. https://doi.org/10.3791/66475.
Taylor, B.C., Steinthal, L.H., Dias, M., Yalamanchili, H.K., Ochsner, S.A., Zapata, G.E., Mehta, N.R., McKenna, N.J., Young, N.L., Nuotio-Antar, A.M. 2024. Histone proteoform analysis reveals epigenetic changes in adult mouse brown adipose tissue in response to cold stress. Epigenetics and Chromatin. 17. Article 12. https://doi.org/10.1186/s13072-024-00536-8.
Zhang, D., Zhao, Y., Zhang, G., Lank, D., Cooke, S., Wang, S., Nuotio-Antar, A., Tong, X., Yin, L. 2024. Suppression of hepatic ChREBPa-CYP2C50 axis-driven fatty acid oxidation sensitizes mice to diet-induced MASLD/MASH. Molecular Metabolism. 85. Article 101957. https://doi.org/10.1016/j.molmet.2024.101957.
Tao, L., Mohammad, M.A., Milazzo, G., Moreno-Smith, M., Patel, T.D., Zorman, B., Badachhape, A., Hernandez, B.E., Wolf, A.B., Zeng, Z., Foster, J.H., Aloisi, S., Sumazin, P., Zu, Y., Hicks, J., Ghaghada, K.B., Putluri, N., Perini, G., Coarfa, C., Barbieri, E. 2022. MYCN-driven fatty acid uptake is a metabolic vulnerability in neuroblastoma. Nature Communications. 13. Article 3728. https://doi.org/10.1038/s41467-022-31331-2.
Cai, J., Jiang, Y., Xu, Y., Jiang, Z., Young, C., Li, H., Ortiz-Guzman, J., Zhuo, Y., Li, Y., Xu, Y., Arenkiel, B.R., Tong, Q. 2024. An excitatory projection from the basal forebrain to the ventral tegmental area that underlies anorexia-like phenotypes. Neuron. 112(3):458-472. https://doi.org/10.1016/j.neuron.2023.11.001.
Xu, Y., Jiang, Z., Li, H., Cai, J., Jiang, Y., Ortiz-Guzman, J., Xu, Y., Arenkiel, B.R., Tong, Q. 2023. Lateral septum as a melanocortin downstream site in obesity development. Cell Reports. 42(5). Article 112502. https://doi.org/10.1016/j.celrep.2023.112502.
Farooqi, I., Xu, Y. 2024. Translational potential of mouse models of human metabolic disease. Cell. https://doi.org/10.1016/j.cell.2024.07.011.
Tu, L., He, Y., Xu, Y. 2023. Anoctamin 4 defines glucose-inhibited neurons in the ventromedial hypothalamus. Neural Regeneration Research. 19(6):1177-1178. https://doi.org/10.4103/1673-5374.385867.
Conde, K., Fang, S., Xu, Y. 2023. Unraveling the serotonin saga: From discovery to weight regulation and beyond - a comprehensive scientific review. Cell & Bioscience. 13(1). Article 143. https://doi.org/10.1186/s13578-023-01091-7.
Liu, H., Qu, N., Gonzalez, N., Palma, M.A., Chen, H., Xiong, J., Choubey, A., Li, Y., Li, X., Yu, M., Liu, H., Tu, L., Zhang, N., Yin, N., Conde, K.M., Wang, M., Bean, J., Han, J., Scarcelli, N.A., Yang, Y., Saito, K., Cui, H., Tong, Q., Sun, Z., Wang, C., He, Y., Xu, Y. 2024. A light-responsive neural circuit suppresses feeding. Journal of Neuroscience. 44(30). Article e2192232024. https://doi.org/10.1523/JNEUROSCI.2192-23.2024.
Edwards, G.A., Wood, C.A., He, Y., Nguyen, Q., Kim, P.J., Gomez-Gutierrez, R., Park, K., Xu, Y., Zurhellen, C., Al-Ramahi, I., Jankowsky, J.L. 2024. TMEM106B coding variant is protective and deletion detrimental in a mouse model of tauopathy. Acta Neuropathologica. 147. Article 61. https://doi.org/10.1007/s00401-024-02701-5.
Yang, W., Jiang, W., Liao, W., Yan, H., Ai, W., Pan, Q., Brashear, W.A., Xu, Y., He, L., Guo, S. 2024. An estrogen receptor a-derived peptide improves glucose homeostasis during obesity. Nature Communications. 15. Article 3410. https://doi.org/10.1038/s41467-024-47687-6.
Liu, H., He, Y., Liu, H., Brouwers, B., Yin, N., Lawler, K., Keogh, J.M., Henning, E., Lee, D., Yu, M., Tu, L., Zhang, N., Conde, K.M., Han, J., Yan, Z., Scarcelli, N.A., Liao, L., Xu, J., Tong, Q., Zheng, H., Sun, Z., Yang, Y., Wang, C., He, Y., Farooqi, I., Xu, Y. 2024. Neural circuits expressing the serotonin 2C receptor regulate memory in mice and humans. Science Advances. https://doi.org/10.1126/sciadv.adl2675.
Li, Y., Cacciottolo, T.M., Yin, N., He, Y., Liu, H., Liu, H., Yang, Y., Henning, E., Keogh, J.M., Lawler, K., Mendes De Oliveira, E., Gardner, E.J., Kentistou, K.A., Laouris, P., Bounds, R., Ong, K.K., Perry, J.R., Barroso, I., Tu, L., Bean, J.C., Yu, M., Conde, K.M., Wang, M., Ginnard, O., Fang, X., Tong, L., Han, J., Darwich, T., Williams, K.W., Yang, Y., Wang, C., Joss, S., Firth, H.V., Xu, Y., Farooqi, I. 2024. Loss of transient receptor potential channel 5 causes obesity and postpartum depression. Cell. https://doi.org/10.1016/j.cell.2024.06.001.
Ortiz-Guzman, J., Swanson, J.L., Tantry, E.K., Kochukov, M., Ung, K., Addison, A.P., Srivastava, S., Belfort, B.D., Ji, E., Dooling, S.W., Chen, S.A., Tong, Q., Arenkiel, B.R. 2024. Cholinergic basal forebrain connectivity to the basolateral amygdala modulates food intake. eNeuro. 11(3). Article ENEURO.0369-23.2024. https://doi.org/10.1523/ENEURO.0369-23.2024.
Han, Y., He, Y., Harris, L., Xu, Y., Wu, Q. 2023. Identification of a GABAergic neural circuit governing leptin signaling deficiency-induced obesity. eLife. 12. Article e82649. https://doi.org/10.7554/eLife.82649.
Xue, Y., Gong, Y., Li, X., Peng, F., Ding, G., Zhang, Z., Shi, J., Savul, I., Xu, Y., Chen, Q., Han, L., Mao, S., Sun, Z. 2023. Sex differences in paternal arsenic-induced intergenerational metabolic effects are mediated by estrogen. Cell & Bioscience. 13. Article 165. https://doi.org/10.1186/s13578-023-01121-4.
Bacha, F., El-Ayash, H., Mohamad, M., Sharma, S., Puyau, M., Kanchi, R., Coarfa, C. 2024. Distinct amino acid profile characterizes youth with or at risk for type 2 diabetes. Diabetes. 73(4):628–636. https://doi.org/10.2337/db23-0375.