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

Location: Children's Nutrition Research Center

2022 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 hedonic (pleasant sensations) values 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 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. Nutritional input is fundamental to the development and treatment of obesity. Consuming an unbalanced diet, particularly one containing a high intake of fat and sugar, can lead to a high prevalence of obesity and its related health complications. Scientists in Houston, Texas, recently found in mice that an essential amino acid (phenylalanine) commonly found in high protein foods like meat, beans, milk and eggs, was necessary in the development of diet-induced obesity. Restriction of phenylalanine protected mice from diet-induced weight gain. Thus, restriction of nutritional phenylalanine intake could be exploited as a potential strategy to treat or prevent obesity.

3. A novel neural pathway can be regulated for the treatment of comorbidity of obesity and mental diseases. Obesity and depression are among the leading causes of disease worldwide and together they jointly form a vicious cycle disrupting the mental and metabolic health for >70% obese patients (i.e. >100 million in the United States and ~500 million worldwide). There has been no effective treatment for this global healthcare issue, however researchers at the Children's Nutrition Research Center in Houston, Texas, discovered how the brain exerts a reciprocal control of feeding of high-fat foods and psychological states. Similar to humans, mice that consumed a high-fat diet not only became obese, but also were anxious and depressed, a condition mediated by a defective brain circuit. When the disruptions were genetically or pharmacologically corrected within this neural circuit, the mice became less anxious and depressed and later lost excess body weight. More importantly, we successfully established a therapy using Food and Drug Administration approved medication for effectively treating this comorbidity. This new regimen displayed striking results that not only eradicate anxiety/depression but also reverse most of the obesity symptoms via a surprising effect to make the subjects voluntarily switch their dieting choice from high-fat foods to a low-fat, carb/protein-enriched healthy diet.

Review Publications
Liu, T., Xu, Y., Yi, C., Tong, Q., Cai, D. 2021. The hypothalamus for whole-body physiology: From metabolism to aging. Protein and Cell. 13(6):394-421. https://doi.org/10.1007/s13238-021-00834-x.
Tu, L., Zhang, N., Conde, K., Bean, J., Wang, C., Xu, Y. 2021. Free-floating immunostaining of mouse brains. The Journal of Visualized Experiments (JoVE). 176. Article e62876. https://doi.org/10.3791/62876.
Mishra, I., Duerrschmid, C., Ku, Z., He, Y., Xie, W., Silva, E., Hoffman, J., Xin, W., Zhang, N., Xu, Y., An, Z., Chopra, A. 2021. Asprosin-neutralizing antibodies as a treatment for metabolic syndrome. eLife. 10. Article e63784. https://doi.org/10.7554/eLife.63784.
Wang, Y., Yang, Y., Wang, M., Wang, S., Jeong, J., Xu, L., Wen, Y., Emontzpoh, C., Atkins, C., Duong, K., Moreno, N., Yuan, X., Hall, D., Dar, W., Feng, D., Gao, B., Xu, Y., Czigany, Z., Colgan, S., Bynon, S., Akira, S., Brown, J., Eltzschig, H., Jacobsen, E., Ju, C. 2021. Eosinophils attenuate hepatic ischemia-reperfusion injury in mice through ST2-dependent IL-13 production. Science Translational Medicine. 13(579). https://doi.org/10.1126/scitranslmed.abb6576.
Fan, S., Xu, Y., Lu, Y., Jiang, Z., Li, H., Morrill, J., Cai, J., Wu, Q., Xu, Y., Xue, M., Arenkiel, B., Huang, C., Tong, Q. 2021. A neural basis for brain leptin action on reducing type 1 diabetic hyperglycemia. Nature Communications. 12. Article 2662. https://doi.org/10.1038/s41467-021-22940-4.
Yoo, E., Li, L., Jia, L., Lord, C., Lee, C., Birnbaum, S., Vianna, C., Berglund, E., Cunningham, K., Xu, Y., Sohn, J., Liu, C. 2021. Galphai/o coupled Htr2c in the paraventricular nucleus of the hypothalamus antagonizes the anorectic effect of serotonin agents. Cell Reports. 37:109997. https://doi.org/10.1016/j.celrep.2021.109997.
Yang, Y., He, Y., Liu, H., Zhou, W., Wang, C., Xu, P., Cai, X., Liu, H., Yu, K., Pei, Z., Hyseni, I., Fukuda, M., Tong, Q., Xu, J., Sun, Z., O'Malley, B., Xu, Y. 2021. Hypothalamic steroid receptor coactivator-2 regulates adaptations to fasting and overnutrition. Cell Reports. 37. Article 110075. https://doi.org/10.1016/j.celrep.2021.110075.
Ding, Y., Liu, Y., Lee, D., Tong, Z., Yu, X., Li, Y., Xu, Y., Lanz, R., O'Malley, B., Xu, J. 2021. Cell lineage tracing links ERa loss in Erbb2-positive breast cancers to the arising of a highly aggressive breast cancer subtype. Proceedings of the National Academy of Sciences (PNAS). 118:21. https://doi.org/10.1073/pnas.2100673118.
Ding, G., Li, X., Hou, X., Zhou, W., Gong, Y., Liu, F., He, Y., Song, J., Wang, J., Basil, P., Li, W., Qian, S., Saha, P., Wang, J., Cui, C., Yang, T., Zou, K., Han, Y., Amos, C., Xu, Y., Chen, L., Sun, Z. 2021. REV-ERB in GABAergic neurons controls diurnal hepatic insulin sensitivity. Nature. 592:763-767. https://doi.org/10.1038/s41586-021-03358-w.
Li, V., He, Y., Contrepois, K., Liu, H., Kim, J., Wiggenhorn, A., Tanzo, J., Tung, A., Lyu, X., Zushin, P., Jansen, R., Michael, B., Loh, K., Yang, A., Carl, C., Voldstedlund, C., Wei, W., Terrell, S., Moeller, B., Arthur, R., Wallis, G., Wetering, K., Stahl, A., Kiens, B., Richter, E., Banik, S., Snyder, M., Xu, Y., Long, J. 2022. An exercise inducible metabolite that suppresses feeding and obesity. Nature. https://doi.org/10.1038/s41586-022-04828-5.
He, Y., Cai, X., Liu, H., Conde, K., Xu, P., Li, Y., Wang, C., Yu, M., He, Y., Liu, H., Liang, C., Yang, T., Yang, Y., Yu, K., Wang, J., Zheng, R., Liu, F., Sun, Z., Heisler, L., Wu, Q., Tong, Q., Zhu, C., Shu, G., Xu, Y. 2021. 5-HT recruits distinct neurocircuits to inhibit hunger-driven and non-hunger-driven feeding. Molecular Psychiatry. 26:7211-7224. https://doi.org/10.1038/s41380-021-01220-z.
Yan, Z., He, Y., Cai, X., Shu, G., Xu, Y. 2021. Eating for hunger or pleasure: A serotonin model. Journal of Molecular Cell Biology. 13(9):693-694. https://doi.org/10.1093/jmcb/mjab055.
Zhang, N., Yan, Z., Liu, H., Yu, M., He, Y., Liu, H., Liang, C., Tu, L., Wang, L., Yin, N., Han, J., Scarcelli, N., Yang, Y., Wang, C., Zeng, T., Chen, L., Xu, Y. 2021. Hypothalamic perineuronal nets are regulated by sex and dietary interventions. Frontiers in Physiology. 12. Article 714104. https://doi.org/10.3389/fphys.2021.714104.
Han, Y., Xia, G., He, Y., He, Y., Farias, M., Xu, Y., Wu, Q. 2021. A hindbrain dopaminergic neural circuit prevents weight gain by reinforcing food satiation. Science Advances. 7(22). https://doi.org/10.1126/sciadv.abf8719.
Han, Y., Xia, G., Srisai, D., Meng, F., He, Y., Ran, Y., He, Y., Farias, M., Hoang, G., Toth, I., Dietrich, M.O., Chen, M., Xu, Y., Wu, Q. 2021. Deciphering an AgRP-serotoninergic neural circuit in distinct control of energy metabolism from feeding. Nature Communications. 12:3525. Article https://doi.org/10.1038/s41467-021-23846-x.
Lusk, S.J., McKinney, A., Hunt, P.J., Fahey, P.G., Patel, J., Chang, A., Sun, J.J., Martinez, V.K., Zhu, P.J., Egbert, J.R., Allen, G., Jiang, X., Arenkiel, B.R., Tolias, A.S., Costa-Mattioli, M., Ray, R.S. 2022. A CRISPR toolbox for generating intersectional genetic mouse models for functional, molecular, and anatomical circuit mapping. BMC Biology. 20. Article 28. https://doi.org/10.1186/s12915-022-01227-0.
Swanson, J.L., Chin, P.S., Romero, J.M., Srivastava, S., Ortiz-Guzman, J., Hunt, P.J., Arenkiel, B.R. 2022. Advancements in the quest to map, monitor, and manipulate neural circuitry. Frontiers in Neural Circuits. 16. Article 886302. https://doi.org/10.3389/fncir.2022.886302.
Ye, H., Feng, B., Wang, C., Saito, K., Yang, Y., Obrahimi, L., Schaul, S., Patel, N., Saenz, L., Luo, P., Lai, P., Torres, V., Kota, M., Dixit, D., Cai, X., Qu, N., Hyseni, I., Yu, K., Jiang, Y., Tong, Q., Sun, Z., Arenkiel, B.R., He, Y., Xu, P., Xu, Y. 2022. An estrogen-sensitive hypothalamus-midbrain neural circuit controls thermogenesis and physical activity. Science Advances. 8(3). Article eabk0185. https://doi.org/10.1126/sciadv.abk0185.
Hunt, P.J., Kochukov, M., Pekarek, B.T., Belfort, B.D., Romero, J.M., Swanson, J.L., Arenkiel, B.R. 2022. Co-transmitting neurons in the lateral septal nucleus exhibit features of neurotransmitter switching. IBRO Neuroscience Reports. 12:390-398. https://doi.org/10.1016/j.ibneur.2022.05.003.