) Obesity is associated with leptin resistance, which limits the potential of leptin therapies. Leptin suppresses food intake and increases energy expenditure by activating its receptors (LepR) in the hypothalamic energy balance circuitry. The food intake arm of the energy balance circuitry has been extensively examined; however, the energy expenditure arm of the circuitry is poorly understood. Moreover, epigenetic reprograming of the hypothalamic energy expenditure circuits has not been explored in the setting of obesity. Leptin stimulates brown and beige adipose tissue thermogenesis, contributing to energy expenditure. Brown and beige fat are required for the maintenance of body temperature homeostasis in rodents, and they also protect against obesity through increasing energy expenditure in both rodents and humans. In preliminary studies, we found that high fat diet (HFD) feeding increases the level of hypothalamic Slug, a nuclear epigenetic factor. We demonstrated that Slug induces methylations and/or acetylation of histone 3 lysine 4 (H3K4) and H3K9, key forms of epigenetic remodeling, in several metabolic gene promoters. We showed that Slug suppresses the expression of Sh2b1, a positive regulator of leptin sensitivity, and stimulates the expression of SOCS3, a negative regulator of leptin signaling. Importantly, LepR+ cell-specific deletion of Slug in mice increases the sympathetic innervation of brown and beige fat, brown/beige fat thermogenesis, energy expenditure, and the body core temperature, but it does not affect food intake. LepR+ cell-specific Slug knockout mice resist HFD- induced leptin resistance, obesity, insulin resistance, and liver steatosis. Hence, we hypothesize that in obesity, aberrant hypothalamic Slug induces leptin resistance selectively in the energy expenditure arm by an epigenetic mechanism. Selective leptin resistance lowers the temperature setpoint, which in turn decreases the body core temperature and energy expenditure through lowering the sympathetic drive in brown/beige fat, thereby contributing to obesity progression. We will test these hypotheses in 3 Aims.
Aim 1 : Determine whether HFD feeding induces leptin resistance by inducing epigenetic reprograming of the hypothalamic Slug+LepR+ circuits via Slug.
Aim 2 : Determine whether HFD feeding impairs the leptin/temperature setpoint/SNS/brown/beige fat pathway by epigenetic mechanisms.
Aim 3 : Determine whether epigenetic regulation of the leptin/temperature setpoint/SNS/brown/beige fat pathway guides energy expenditure, body weight, and metabolism. This project is significant because it introduces the novel concepts of epigenetic reprograming of the hypothalamic energy balance circuits and regulation of obesity progression by the temperature setpoint and is expected to lead to new approaches in therapies targeting obesity.

Public Health Relevance

There is a huge gap in the understanding of the genomic and epigenetic regulation of brain circuits that control body weight and nutrient metabolism, thus limiting our ability to develop effective therapies against obesity and diabetes. This project will identify the genetic and epigenetic machinery by which Slug protein controls body weight and blood glucose levels. The outcomes of this project are expected to lead to new prevention methods and treatments against obesity and diabetes by targeting the Slug pathways in the brain.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
3R01DK114220-04S1
Application #
10197297
Study Section
Molecular and Cellular Endocrinology Study Section (MCE)
Program Officer
Cooke, Brad
Project Start
2017-08-01
Project End
2021-06-30
Budget Start
2020-07-01
Budget End
2021-06-30
Support Year
4
Fiscal Year
2020
Total Cost
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Physiology
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
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Xiong, Yi; Torsoni, Adriana Souza; Wu, Feihua et al. (2018) Hepatic NF-kB-inducing kinase (NIK) suppresses mouse liver regeneration in acute and chronic liver diseases. Elife 7:
Liu, Yan; Jiang, Lin; Sun, Chengxin et al. (2018) Insulin/Snail1 axis ameliorates fatty liver disease by epigenetically suppressing lipogenesis. Nat Commun 9:2751