The incidence of obesity and type 2 diabetes has reached global epidemic prevalence in both the developed and developing countries. Patients with glucocorticoid (GC) excess (Cushing's syndrome) develop reversal obesity and insulin resistance. However, patients with idiopathic obesity and/or metabolic syndrome do not have elevated circulating GC levels. Metabolic tissues such as liver and adipose tissue solely express 112- hydroxysteroid dehydrogenase (112-HSD1) where it acts in intact cells and organs as a NADPH-dependent reductase to generate active cortisol from inert circulating cortisone. 112-HSD1 therefore plays a crucial role in local steroid reactivation. In the endoplasmic reticulum (ER) lumen, hexose-6-phosphate dehydrogenase (H6PDH) converts glucose-6-phosphate (G6P) and NADP to generate NADPH. This reaction requires the G6P transporter (G6PT) to maintain its metabolic substrateG6P availability. This generates NADPH which is utilized by 112-HSD1, thus constituting a connection of H6PDH and 112-HSD1 in regulation of tissue GC regeneration. In support of this, H6PDH knockout mice are unable to regenerate tissue GCs and impaired 112- HSD1 activity. We recently reported that reduction of H6PDH expression leads to suppressed hepatic and adipose 112-HSD1 activity that may contribution to insulin sensitivity and weight loss in a high- fat diet model of obesity. Our new preliminary data show that tissue-specific activation of H6PDH expression leads to up- regulation of 112-HSD1 activity that correlated with insulin resistance and obesity in type 2 diabetic animal models. We therefore hypothesize that H6PDH is the critical determinant of whether 112-HSD1 can regenerate GCs that contributes to the pathogenesis of type 2 diabetes and obesity. In this grant, we will examine the impact of H6PDH on insulin signaling action through manipulation of H6PDH to regulation of 12-HSD1 amplifying GC regeneration by using siRNA technology in intact mouse hepatocytes and adipocytes. These cell culture studies will be reinforced by treatment of animals with specific H6PDH or G6PT siRNA in a viral vector to define that inhibition of H6PDH could provide therapeutic benefits for diabetes and obesity. We believe that blocking the effects of H6PDH on 112-HSD1 may be a new strategy in the effective treatment of diabetes/or obesity Public Health Relevance: Patients who produce too much cortisol develop obesity and in some cases, type 2 diabetes. We posit this is due, in part, to the H6PDH-induced 112-HSD1 amplifying tissue glucocorticoid (GC) regeneration. Blocking the effects of H6PDH on 112-HSD1 may represent a new strategy in the effective treatment of type 2 diabetes and obesity through reduction of tissue GC availability mediating insulin sensitivity and glucose homeostasis.

Public Health Relevance

Patients who produce too much cortisol develop obesity and in some cases, type 2 diabetes. We posit this is due, in part, to the H6PDH-induced 11?-HSD1 amplifying tissue glucocorticoid (GC) regeneration. Blocking the effects of H6PDH on 11?-HSD1 may represent a new strategy in the effective treatment of type 2 diabetes and obesity through reduction of tissue GC availability mediating insulin sensitivity and glucose homeostasis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Enhancement Award (SC1)
Project #
5SC1DK087655-04
Application #
8305688
Study Section
Special Emphasis Panel (ZGM1-MBRS-9 (NP))
Program Officer
Agodoa, Lawrence Y
Project Start
2009-09-01
Project End
2014-07-31
Budget Start
2012-08-01
Budget End
2013-07-31
Support Year
4
Fiscal Year
2012
Total Cost
$317,250
Indirect Cost
$92,250
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
Wang, Ying; Liu, Limei; Du, Hanze et al. (2014) Transgenic overexpression of hexose-6-phosphate dehydrogenase in adipose tissue causes local glucocorticoid amplification and lipolysis in male mice. Am J Physiol Endocrinol Metab 306:E543-51
Liu, Limei; Nagashima, Kazuaki; Yasuda, Takao et al. (2013) Mutations in KCNJ11 are associated with the development of autosomal dominant, early-onset type 2 diabetes. Diabetologia 56:2609-18
Ren, Xiuhai; Lutfy, Kabirullah; Mangubat, Michael et al. (2013) Alterations in phosphorylated CREB expression in different brain regions following short- and long-term morphine exposure: relationship to food intake. J Obes 2013:764742
Du, Hanze; Liu, Limei; Wang, Ying et al. (2013) Specific reduction of G6PT may contribute to downregulation of hepatic 11ýý-HSD1 in diabetic mice. J Mol Endocrinol 50:167-78
Nie, Ying; Ferrini, Monica G; Liu, Yanjun et al. (2013) Morphine treatment selectively regulates expression of rat pituitary POMC and the prohormone convertases PC1/3 and PC2. Peptides 47:99-109
Sano, S; Nakagawa, Y; Yamaguchi, R et al. (2012) Carbenoxolone alters the morphology of adipose tissues and downregulates genes involved in adipogenesis, glucose transport and lipid metabolism in high-fat diet-fed mice. Horm Metab Res 44:15-20
Lutfy, Kabirullah; Aimiuwu, Otaren; Mangubat, Michael et al. (2012) Nicotine stimulates secretion of corticosterone via both CRH and AVP receptors. J Neurochem 120:1108-16
Mangubat, Michael; Lutfy, Kabirullah; Lee, Martin L et al. (2012) Effect of nicotine on body composition in mice. J Endocrinol 212:317-26
Nagata, E; Nakagawa, Y; Yamaguchi, R et al. (2011) Altered gene expressions of ghrelin, PYY, and CCK in the gastrointestinal tract of the hyperphagic intrauterine growth restriction rat offspring. Horm Metab Res 43:178-82
Wang, Y; Nakagawa, Y; Liu, L et al. (2011) Tissue-specific dysregulation of hexose-6-phosphate dehydrogenase and glucose-6-phosphate transporter production in db/db mice as a model of type 2 diabetes. Diabetologia 54:440-50

Showing the most recent 10 out of 11 publications