Obesity and type-2 diabetes (T2D) are two epidemic problems, but partly due to limited understandings on the underlying mechanisms, currently there are inadequate interventional approaches to treat or prevent these diseases. Having appreciated that IKK?/NF-?B-dependent inflammation mediates neuronal dysregulations in the brain and particularly the hypothalamus, the long-term objective of this research is to study the involved neural connections, molecular pathways, and physiological basis which can eventually lead to new strategies in treating and preventing these diseases. Preliminary studies have focused on astroglia which account for majority of brain cells, and using astroglia-specific mouse models with IKK?/NF-?B activation or inhibition, it was revealed that IKK?/NF-?B activation in astroglia causes neuronal inflammation leading to energy imbalance that promotes obesity development. Conversely, IKK?/NF-?B inhibition in astroglia can protect neuronal functions to provide anti-obesity benefits. Hence, this project hypothesizes that astroglial IKK?/NF-?B is sensitively activated by overnutrition to adversely affect neurons and cause metabolic dysregulations that underlie the development of obesity and T2D;conversely, IKK?/NF-?B inhibition in astroglia help improve the micro-environment of neurons leading to improved neuronal functions and thus counteraction against these diseases.
Three Specific Aims are propsoed: (1) Study the action of astroglial IKK?/NF-?B in inducing neuronal inflammation;(2) Study the role of astroglial IKK?/NF-?B in affecting neuronal metabolic regulation;(3) Study the disease relevance of astroglial IKK?/NF-?B and its crosstalk with neurons. A combined genetic and gene delivery appraoches together with relevant neural analyses will be used to carry out these Aims. All key animal models, reagents and techniques have been established, and supportive preliminary results have been obtained. Overall, successful completion of this project will significantly clarify the brain mechanism of obesity and T2D, and enlighten the development of interventional strategies against these diseases.

Public Health Relevance

Eating disorders and obesity can arise from overnutrition-induced inflammation in the brain and particularly the comprised the hypothalamus which is known as the master regulator of feeding and body weight balance. This project will use mouse models to investigate the role of a proinflammatory system in a subtype of neural cells in affecting the micro-environment of hypothalamic regulation, and if inhibition of this proinflammatory process is beneficial in counteracting obesity and related diabetic changes. Successful completion of this study will help to understand the brain mechanism of obesity and co-morbidities and develop novel interventional strategies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK078750-07
Application #
8626389
Study Section
Integrative Physiology of Obesity and Diabetes Study Section (IPOD)
Program Officer
Hyde, James F
Project Start
2007-07-01
Project End
2018-04-30
Budget Start
2014-05-01
Budget End
2015-04-30
Support Year
7
Fiscal Year
2014
Total Cost
$442,204
Indirect Cost
$177,411
Name
Albert Einstein College of Medicine
Department
Pharmacology
Type
Schools of Medicine
DUNS #
110521739
City
Bronx
State
NY
Country
United States
Zip Code
10461
Han, Cheng; Wu, Wenhe; Ale, Albert et al. (2016) Central Leptin and Tumor Necrosis Factor-α (TNFα) 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
Tang, Yizhe; Purkayastha, Sudarshana; Cai, Dongsheng (2015) Hypothalamic microinflammation: a common basis of metabolic syndrome and aging. Trends Neurosci 38:36-44
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
Li, Juxue; Tang, Yizhe; Purkayastha, Sudarshana et al. (2014) Control of obesity and glucose intolerance via building neural stem cells in the hypothalamus. Mol Metab 3:313-24
Yan, Jingqi; Zhang, Hai; Yin, Ye et al. (2014) Obesity- and aging-induced excess of central transforming growth factor-β potentiates diabetic development via an RNA stress response. Nat Med 20:1001-8
Zhang, Hai; Wu, Chenguang; Chen, Qiaofen et al. (2013) Treatment of obesity and diabetes using oxytocin or analogs in patients and mouse models. PLoS One 8:e61477
Zhang, Guo; Li, Juxue; Purkayastha, Sudarshana et al. (2013) Hypothalamic programming of systemic ageing involving IKK-β, NF-κB and GnRH. Nature 497:211-6
Purkayastha, Sudarshana; Cai, Dongsheng (2013) Neuroinflammatory basis of metabolic syndrome. Mol Metab 2:356-63
Liu, Tiewen; Cai, Dongsheng (2013) Counterbalance between BAG and URX neurons via guanylate cyclases controls lifespan homeostasis in C. elegans. EMBO J 32:1529-42

Showing the most recent 10 out of 27 publications