Obesity and type 2 diabetes (T2DM) have become public health problems of epidemic proportions and much effort is being undertaken to understand the molecular mechanisms underlying the pathogenesis of these conditions to design new treatments. Obesity dramatically increases the risk of developing T2DM and patients with glucocorticoid (GC) excess (Cushing's syndrome) produce visceral obesity and diabetes, but circulating GC levels are not elevated in the vast majority of patients with typical obesity and metabolic syndrome (MS). However, many typical obesity and MS can be accounted for by abnormally increased regeneration of GCs within adipose tissue by an intracellular endoplasmic reticulum (ER) lumen-resident enzyme, 11-hydroxysteroid dehydrogenase (11-HSD1) that can generate active cortisol from inactive cortisone and thus amplifies intracellular GC action despite unaltered plasma GC levels in obesity and MS. Pre-receptor activation of GCs via 11-HSD1 is thus regarded as a common molecular etiology for obesity and MS. However, 11-HSD1 within the ER is crucially dependent on the enzyme hexose-6-phosphate dehydrogenase (H6PDH) to maintain its cofactor NADPH availability. In the ER lumen, H6PDH can metabolize glucose-6-phosphate (G6P) and generates NADPH from NADP and requires the G6P transporter to maintain its metabolic substrate G6P levels. H6PDH is thus able to couple the regulation of cellular G6P metabolism and GC signaling linked to the pathogenesis of T2DM and obesity. Indeed, we have shown that the increased adipose H6PDH expression leading to up-regulation of 11-HSD1 in obese diabetic mice is similar to that found in adipose tissue from T2DM patients. However, the functional consequences of altered adipose H6PDH expression are unknown. Using our unique transgenic mouse overexpression of H6PDH selectively in adipose tissue, we have observed that these mice have abnormally increased adipose corticosterone production and cellular G6P metabolism and exhibited the adverse metabolic phenotypes with hyperglycemia, visceral fat accumulation, hyperlipidemia, and insulin resistance. We thus hypothesize that adipose H6PDH plays an important role in the pathophysiology of obesity and insulin resistance, and can be manipulated to provide potential strategies for the treatment of MS. In this grant, we will explore the impact of adipose H6PDH on glucose homeostasis and insulin sensitivity in vivo using our unique existing H6PDH transgenic model. We will also directly examine the role of altered H6PDH expression in insulin signaling action through manipulation of H6PDH to regulation of cellular GC regeneration and G6P metabolism by using siRNA technology in intact mouse adipocyte cells. This will be facilitated by generation and evaluation of a H6PDH fat-specific knockout mouse. We believe that manipulating the role and impact of H6PDH on adipose function and homeostasis will provide new strategies that may translate into novel therapies for patients with T2DM and MS.

Public Health Relevance

The number of individuals affected by T2DM and obesity is increasing at an alarming rate and are often associated with dysregulation of glucose and glucocorticoid metabolism. Much effort is therefore needed to be undertaken to identify the reasons for this disease to design new treatments. We recently reported a gene called H6PDH that can regulate cortisol hormone metabolism and glucose homeostasis. We believe that effective manipulation of H6PDH may provide a new therapeutic strategy for the treatment of T2DM and obesity.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Enhancement Award (SC1)
Project #
5SC1DK104821-08
Application #
9113569
Study Section
Special Emphasis Panel (ZGM1)
Program Officer
Agodoa, Lawrence Y
Project Start
2009-09-01
Project End
2018-07-31
Budget Start
2016-08-01
Budget End
2017-07-31
Support Year
8
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Charles R. Drew University of Medicine & Science
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
785877408
City
Los Angeles
State
CA
Country
United States
Zip Code
90059
Dong, Yunzhou; Fernandes, Conrad; Liu, Yanjun et al. (2017) Role of endoplasmic reticulum stress signalling in diabetic endothelial dysfunction and atherosclerosis. Diab Vasc Dis Res 14:14-23
Tian, Jiayi; Liu, Yanjun; Jiang, Yanfang et al. (2017) Association of single nucleotide polymorphisms of IL23R and IL17 with necrotizing enterocolitis in premature infants. Mol Cell Biochem 430:201-209
Dong, Yunzhou; Cai, Xue; Wu, Yong et al. (2017) Insights from Genetic Model Systems of Retinal Degeneration: Role of Epsins in Retinal Angiogenesis and VEGFR2 Signaling. J Nat Sci 3:
Yao, Fan; Chen, Li; Fan, Zheng et al. (2017) Interplay between H6PDH and 11?-HSD1 implicated in the pathogenesis of type 2 diabetes mellitus. Bioorg Med Chem Lett 27:4107-4113
Lutfy, K; Parikh, D; Lee, D L et al. (2016) Prohormone convertase 2 (PC2) null mice have increased mu opioid receptor levels accompanied by altered morphine-induced antinociception, tolerance and dependence. Neuroscience 329:318-25
Dong, Yunzhou; Wu, Hao; Rahman, H N Ashiqur et al. (2016) Motif mimetic of epsin perturbs tumor growth and metastasis. J Clin Invest 126:1607
Yan, C; Yang, H; Wang, Y et al. (2016) Increased glycogen synthase kinase-3? and hexose-6-phosphate dehydrogenase expression in adipose tissue may contribute to glucocorticoid-induced mouse visceral adiposity. Int J Obes (Lond) 40:1233-41
Wang, Ying; Yan, Chaoying; Liu, Limei et al. (2015) 11?-Hydroxysteroid dehydrogenase type 1 shRNA ameliorates glucocorticoid-induced insulin resistance and lipolysis in mouse abdominal adipose tissue. Am J Physiol Endocrinol Metab 308:E84-95
Dong, Yunzhou; Wu, Hao; Rahman, H N Ashiqur et al. (2015) Motif mimetic of epsin perturbs tumor growth and metastasis. J Clin Invest 125:4349-64
Zhuang, Langen; Zhao, Yu; Zhao, Weijing et al. (2015) The E23K and A190A variations of the KCNJ11 gene are associated with early-onset type 2 diabetes and blood pressure in the Chinese population. Mol Cell Biochem 404:133-41

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