Energy balance and body weight control are regulated by hypothalamic neurons through sensing nutrients; however, the underlying molecular basis is still much unclear. Hypoxia-inducible factor (HIF) has recently been known to be activated by normoxic metabolic signals, and our recent publication showed that hypothalamic HIF2?/HIF? responds to glucose and HIF knockout in hypothalamic neurons are obssogenic. Therefore, the objective of this research is to study hypothalamic nutrient-sensing mechanism and its importance in metabolic physiology or disease. Our recent preliminary studies further revealed that physiological levels of glucose or leucine both activated hypothalamic HIF2? to be causally associated with diet-induced metabolic responses. Hence, the hypothesis of this proposal is that hypothalamic HIF is important for diet-induced metabolic control in terms of appetite and energy expenditure (including the forms of diet-induced spontaneous physical activity and thermogenesis). This hypothesis leads to prediction that while hypothalamic HIF inhibition causes energy imbalance and obesity, hypothalamic HIF gene delivery can improve energy balance to counteract dietary obesity.
Three Specific Aims are propsoed to: (1) study the effects of nutrients on hypothalamic HIF and the involved molecular mechanism; (2) study the effects of hypothalamic HIF manipulations in appetite and energy expenditure control (including diet-induced spontaneous physical activity and diet-induced thermogenesis), and also study the molecular mediators and the sympathetic nervous system-directed physiological mechanism; (3) study effects of hypothalamic HIF inhibition or activation on dietary obesity. Experimental approaches will be significantly based on analyses of metabolic and behavioral physiology as well as HIF pathway in normal mice and the models with hypothalamic HIF manipulations in relation with various nutrient deliveries. Success of this project can lead to a new paradigm of energy balance control and a new target for treating obesity.
Body weight control is importantly regulated by a brain region through sensing nutrients in the body; however, it is poorly appreciated regarding how this nutrient-sensing process is induced in this brain region. Recently, we have identified a molecular pathway that has actions in this brain region to sense nutrients and control energy balance, and in this context, we propose to study how this molecular pathway works in this brain region, what are the molecular mediators that are upstream and downstream of this pathway, if this pathway is important for weight control, and whether this pathway can be targeted to treat or prevent obesity.
|Alé, Albert; Zhang, Yalin; Han, Cheng et al. (2017) Obesity-associated extracellular mtDNA activates central TGF? pathway to cause blood pressure increase. Am J Physiol Endocrinol Metab 312:E161-E174|
|Zhang, Yalin; Reichel, Judith M; Han, Cheng et al. (2017) Astrocytic Process Plasticity and IKK?/NF-?B in Central Control of Blood Glucose, Blood Pressure, and Body Weight. Cell Metab 25:1091-1102.e4|
|Zhang, Yalin; Kim, Min Soo; Jia, Baosen et al. (2017) Hypothalamic stem cells control ageing speed partly through exosomal miRNAs. Nature 548:52-57|
|Yu, Bin; Cai, Dongsheng (2017) Neural Programmatic Role of Leptin, TNF?, Melanocortin, and Glutamate in Blood Pressure Regulation vs Obesity-Related Hypertension in Male C57BL/6 Mice. Endocrinology 158:1766-1775|
|Khor, Sinan; Cai, Dongsheng (2017) Hypothalamic and inflammatory basis of hypertension. Clin Sci (Lond) 131:211-223|
|Han, Cheng; Rice, Matthew W; Cai, Dongsheng (2016) Neuroinflammatory and autonomic mechanisms in diabetes and hypertension. Am J Physiol Endocrinol Metab 311:E32-41|
|Han, Cheng; Wu, Wenhe; Ale, Albert et al. (2016) Central Leptin and Tumor Necrosis Factor-? (TNF?) in Diurnal Control of Blood Pressure and Hypertension. J Biol Chem 291:15131-42|
|Kim, Min Soo; Yan, Jingqi; Wu, Wenhe et al. (2015) Rapid linkage of innate immunological signals to adaptive immunity by the brain-fat axis. Nat Immunol 16:525-33|
|Zhang, Yumin; Liu, Gang; Yan, Jingqi et al. (2015) Metabolic learning and memory formation by the brain influence systemic metabolic homeostasis. Nat Commun 6:6704|
|Yan, Jingqi; Zhang, Hai; Yin, Ye et al. (2014) Obesity- and aging-induced excess of central transforming growth factor-? potentiates diabetic development via an RNA stress response. Nat Med 20:1001-8|