Location: Children's Nutrition Research Center
2023 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: 3092-51000-064-01S (Project #1), 3092-51000-064-02S (Project #2), and 3092-51000-062-05S (Project #3).
Accomplishments
1. A new way to reduce eating in the absence of hunger. Hunger can drive humans and animals to eat, but in the absence of hunger, eating can also be triggered by the hedonic (pleasant sensations) value of foods. This "pleasure-driven" eating is a contributing factor to obesity. Researchers at the Children's Nutrition Research Center in Houston, Texas, have 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 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 basal forebrain circuits that mediate food seeking or avoidance. From seeking out preferred foods or avoiding others, neural circuits in the brain, specifically the basal forebrain, guide eating behaviors. Understanding how the brain processes food-related cues is essential towards maintaining healthy eating habits, as well as treating eating disorders. Researchers at the Children's Nutrition Research Center in Houston, Texas, have been using genetically engineered mouse models to mark, map, and manipulate basal forebrain circuits to determine their roles in identifying, consuming, or avoiding different foods. In mouse models, we have devised new ways to genetically label and manipulate basal forebrain circuitry and have also evaluated how they impact feeding. We have identified distinct neural circuits extending from the basal forebrain to both reward and aversion centers and found that this circuitry dynamically processes food-related cues to govern feeding. Revealing these circuits holds promise for targeting them for using various approaches to treat eating disorders such as obesity and/or anorexia.
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 that an essential amino acid (phenylalanine) 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
Cai, X., Liu, H., Feng, B., Yu, M., He, Y., Liu, H., Liang, C., Yang, Y., Tu, L., Zhang, N., Wang, L., Yin, N., Han, J., Yan, Z., Wang, C., Xu, P., Wu, Q., Tong, Q., He, Y., Xu, Y. 2022. A D2 to D1 shift in dopaminergic inputs to midbrain 5-HT neurons causes anorexia in mice. Nature Neuroscience. 25:646-658. https://doi.org/10.1038/s41593-022-01062-0.
He, Y., Brouwers, B., Liu, H., Liu, H., Lawler, K., Mendes De Oliveira, E., Lee, D., Yang, Y., Cox, A.R., Keogh, J.M., Henning, E., Bounds, R., Perdikari, A., Ayinampudi, V., Wang, C., Yu, M., Tu, L., Zhang, N., Yin, N., Han, J., Scarcelli, N., Yan, Z., Conde, K., Potts, C., Bean, J.C., Wang, M., Hartig, S.M., Liao, L., Xu, J., Barroso, I., Mokrosinski, J., Xu, Y., I Sadaf, F. 2022. Human loss-of-function variants in the serotonin 2C receptor associated with obesity and maladaptive behavior. Nature Medicine. 28:2537–2546. https://doi.org/10.1038/s41591-022-02106-5.
Cai, J., Chen, J., Ortiz-Guzman, J., Huang, J., Arenkiel, B.R., Wang, Y., Zhang, Y., Shi, Y., Tong, Q., Zhan, C. 2023. AgRP neurons are not indispensable for body weight maintenance in adult mice. Cell Reports. 42(7). Article 112789. https://doi.org/10.1016/j.celrep.2023.112789.
Li, H., Xu, Y., Jiang, Y., Jiang, Z., Otiz-Guzman, J., Morrill, J., Cai, J., Mao, Z., Xu, Y., Arenkiel, B., Huang, C., Tong, Q. 2023. The melanocortin action is biased toward protection from weight loss in mice. Nature Communications. 14. Article 2200. https://doi.org/10.1038/s41467-023-37912-z.
Mishra, I., Xie, W., Bournat, J.C., He, Y., Wang, C., Silva, E., Liu, H., Ku, Z., Chen, Y., Erokwu, B.O., Jia, P., Zhao, Z., An, Z., Flask, C.A., He, Y., Xu, Y., Chopra, A.R. 2022. Protein tyrosine phosphatase receptor d serves as the orexigenic asprosin receptor. Cell Metabolism. 34(4):549-563. https://doi.org/10.1016/j.cmet.2022.02.012.
Pei, Z., He, Y., Bean, J., Yang, Y., Liu, H., Yu, M., Yu, K., Hyseni, I., Cai, X., Liu, H., Qu, N., Tu, L., Conde, K., Wang, M., Li, Y., Yin, N., Zhang, N., Han, J., Potts, C., Scarcelli, N., Yan, Z., Xu, P., Wu, Q., He, Y., Xu, Y., Wang, C. 2022. Gabra5 plays a sexually dimorphic role in POMC neuron activity and glucose balance. Frontiers in Endocrinology. 13. Article 889122. https://doi.org/10.3389/fendo.2022.889122.
Swanson, J.L., Ortiz-Guzman, J., Srivastava, S., Chin, P., Dooling, S.W., Hanson Moss, E., Kochukov, M., Hunt, P.J., Patel, J.M., Pekarek, B.T., Tong, Q., Arenkiel, B.R. 2022. Activation of basal forebrain-to-lateral habenula circuitry drives reflexive aversion and suppresses feeding behavior. Scientific Reports. 12. Article 22044. https://doi.org/10.1038/s41598-022-26306-8.
Liu, H., He, Y., Bai, J., Zhang, C., Zhang, F., Yang, Y., Luo, H., Yu, M., Liu, H., Tu, L., Zhang, N., Yin, N., Han, J., Yan, Z., Scarcelli, N., Conde, K., Wang, M., Bean, J., Potts, C., Wang, C., Hu, F., Liu, F., Xu, Y. 2023. Hypothalamic Grb10 enhances leptin signaling and promotes weight loss. Nature Metabolism. 5:147–164. https://doi.org/10.1038/s42255-022-00701-x.
Yu, M., Bean, J., Liu, H., He, Y., Yang, Y., Cai, X., Yu, K., Pei, Z., Liu, H., Tu, L., Conde, K., Wang, M., Li, Y., Yin, N., Zhang, N., Han, J., Scarcelli, N., Xu, P., He, Y., Xu, Y., Wang, C. 2022. SK3 in POMC neurons plays a sexually dimorphic role in energy and glucose homeostasis. Cell & Bioscience. 12. Article 170. https://doi.org/10.1186/s13578-022-00907-2.
Liu, H., Cai, X., He, Y., Xu, Y. 2022. Hyperactivity of a midbrain dopamine to 5-HT circuit causes anorexia. Journal of Molecular Cell Biology. 14(5). https://doi.org/10.1093/jmcb/mjac035.
Juras, P.K., Racioppi, L., Mukherjee, D., Artham, S., Gao, X., D'Agostino, L.A., Chang, C., McDonnell, D.P. 2023. Increased CaMKK2 expression is an adaptive response that maintains the fitness of tumor-infiltrating natural killer cells. Cancer Immunology Research. 11(1):109-1022. https://doi.org/10.1158/2326-6066.CIR-22-0391.
Tu, L., Fukuda, M., Tong, Q., Xu, Y. 2022. The ventromedial hypothalamic nucleus watchdog of whole-body glucose homeostasis. Cell & Bioscience. 12. Article 71. https://doi.org/10.1186/s13578-022-00799-2.
Wang, M., Yang, Y., Xu, Y. 2023. Brain nuclear receptors and cardiovascular function. Cell & Bioscience. 13. Article 14. https://doi.org/10.1186/s13578-023-00962-3.
Masschelin, P.M., Saha, P., Ochsner, S.A., Cox, A.R., Kim, K.H., Felix, J.B., Sharp, R., Li, X., Tan, L., Park, J.H., Wang, L., Putluri, V., Lorenzi, P.L., Nuotio-Antar, A.M., Sun, Z., Kaipparettu, B.A., Putluri, N., Moore, D.D., Summers, S.A., McKenna, N.J., Hartig, S.M. 2023. Vitamin B2 enables regulation of fasting glucose availability. eLife. 12. Article e84077. https://doi.org/10.7554/eLife.84077.
