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 #
5R01DK078750-11
Application #
9253384
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
2017-05-01
Budget End
2018-04-30
Support Year
11
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Albert Einstein College of Medicine, Inc
Department
Type
DUNS #
079783367
City
Bronx
State
NY
Country
United States
Zip Code
10461
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
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
Zhang, Yalin; Kim, Min Soo; Jia, Baosen et al. (2017) Hypothalamic stem cells control ageing speed partly through exosomal miRNAs. Nature 548:52-57
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
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
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
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

Showing the most recent 10 out of 33 publications