Source: AUBURN UNIVERSITY submitted to
CURCUMIN AS A FUNCTIONAL FOOD FOR WEIGHT MANAGEMENT AND PREVENTION OF TYPE 2 DIABETES
Sponsoring Institution
National Institute of Food and Agriculture
Project Status
TERMINATED
Funding Source
HATCH
Reporting Frequency
Annual
Accession No.
0225478
Grant No.
(N/A)
Project No.
ALA043-1-11001
Proposal No.
(N/A)
Multistate No.
(N/A)
Program Code
(N/A)
Project Start Date
Oct 1, 2011
Project End Date
Sep 30, 2016
Grant Year
(N/A)
Project Director
Mathews, S. T.
Recipient Organization
AUBURN UNIVERSITY
108 M. WHITE SMITH HALL
AUBURN,AL 36849
Performing Department
Nutrition and Food Science
Non Technical Summary
Plant derivatives with purported anti-diabetic properties have been used in folk medicine, traditional healing systems, and as complementary and alternative therapy. Curcumin, the bioactive component of curry spice turmeric and its related structures, curcuminoids, possess potent antioxidant and anti-inflammatory properties. It is now well recognized that inflammation plays a major role in the pathophysiology of obesity and diabetes. Several lines of evidence suggest that curcumin may play a beneficial role in diabetes, both by lowering blood glucose levels and by ameliorating the long-term complications of diabetes. However, current understanding of the mechanism of curcumin action is rudimentary and is limited to its antioxidant and anti-inflammatory effects. Our long-term goal is to understand the impact of increased consumption of curcumin either from turmeric or obtained through dietary supplementation, in weight management and alleviation of chronic conditions such as diabetes, contributing to an improved, healthier lifestyle. The overall objective is to study the molecular mechanism(s) dictating curcumin's role obesity prevention and in the regulation of insulin action. Our central hypothesis is that curcumin decreases inflammation, increases fat oxidation, inhibits fat storage, and modulates insulin action by activating PPARgamma and AMPK, two critical targets involved in the modulation of insulin action and sensitivity. Preliminary data generated in our laboratory indicate that, at levels comparable to its bioavailability, curcumin modulates gluconeogenic gene expression in the liver, and induces transcriptional activation of PPAR-gamma, without inducing fat cell differentiation. This proposal aims to evaluate efficacy of curcumin's anti-obesity and anti-diabetic effects in an animal model of diet-induced obesity and characterize its molecular mechanisms. The proposed studies, evaluating efficacy of obesity resistance and characterizing curcumin's role in glucose regulation, may serve to validate curcumin as a natural compound in the prevention of obesity and improvement of insulin action. Further, curcumin may potentially complement the conventional treatment of insulin resistant conditions, including obesity, pre-diabetes, metabolic syndrome, and type 2 diabetes.
Animal Health Component
(N/A)
Research Effort Categories
Basic
100%
Applied
(N/A)
Developmental
(N/A)
Classification

Knowledge Area (KA)Subject of Investigation (SOI)Field of Science (FOS)Percent
70222351010100%
Knowledge Area
702 - Requirements and Function of Nutrients and Other Food Components;

Subject Of Investigation
2235 - Herbs and spices;

Field Of Science
1010 - Nutrition and metabolism;
Goals / Objectives
Goals and Objectives: The goal of this proposal is to evaluate curcumin, the specific bioactive food component of turmeric, as a functional food in the prevention of obesity and type 2 diabetes. Several reports suggest that curcumin may play a beneficial role in diabetes, both by lowering blood glucose levels and by ameliorating the long-term complications of diabetes. We have recently shown that curcumin activates AMPK, and suppresses hepatic gluconeogenic gene expression, suggesting that curcumin can lower fasting blood glucose levels and therefore may play a potential role in the management of diabetes. Our central hypothesis is that curcumin inhibits fat storage and modulates insulin action and glucose metabolism by (a) inhibiting adipocyte differentiation, (b) by activating PPARgamma and eliciting a favorable adipokine release, and (c) activating 5'-AMP-activated protein kinase (AMPK), increasing fat oxidation and downregulating gluconeogenic gene expression. This hypothesis was formulated based on preliminary data generated in our laboratory which show that curcumin induces transcriptional activation of PPARgamma without adipogenesis, and is an activator of AMPK. To test our hypothesis, we propose the following objectives: Objective 1: Evaluate efficacy of curcumin's anti-obesity and anti-diabetic effects in an animal model of diet-induced obesity Objective 2: Characterize mechanism(s) by which curcumin exerts anti-obesity effects and improves insulin action and glucose metabolism (transcriptional activation of PPARgamma but without adipocyte differentiation) Expected Outputs: On the strength of the preliminary findings, we are enthusiastic that the proposed studies will demonstrate efficacy of curcumin in preclinical animal models and offer a mechanistic basis for curcumin's anti-obesity and anti-diabetic effects. Our preliminary data suggests that this natural compound and its metabolite, tetrahydrocurcumin, may exert potent effects at concentrations comparable to its bioavailability. We expect that curcumin, unlike the thiazolidinedione (TZD) class of drugs, such as rosiglitazone, which increases body weight while improving insulin sensitivity, may contribute to a lower body weight, lower inflammatory markers, and an overall improvement of glucose metabolism by activating PPARgammaand selectively upregulating target genes, including adiponectin. It is anticipated that AMPK activation will lead to an increased fat oxidation and suppression of hepatic glucose production (HGP). Since a primary defect of type 2 diabetes is uncontrolled HGP, because of the inability of insulin to effectively suppress HGP, curcumin's effects on suppression of HGP, may contribute to an overall improvement of glucose metabolism. Timeline: Year 01: Characterize mechanisms in intact cell culture, in vitro systems, start high-fat feeding study, and initiate animal studies; submit manuscript on intact cell studies. Year 02: Complete mechanistic studies in vitro, high-fat diet studies; submit 2 manuscripts, one on curcumin's effects on obesity prevention and another on improving insulin sensitivity in HF-fed animals.
Project Methods
The above goals and objectives will be attained using a combination of in vitro tests, cell-culture assays, and animal studies. We will evaluate the efficacy of curcumin's anti-obesity and anti-diabetic effects in a mouse model of diet-induced obesity. We will monitor body weight, blood glucose, insulin and conduct oral glucose and insulin tolerance tests in mice to assay for improvements in glycemic status and insulin sensitivity. MRI imaging for whole body fat/lean tissue composition will also be performed. Further gene expression analysis of fat oxidation genes will be conducted. Secondly, we will characterize mechanisms by which curcumin exerts in anti-obesity effects and improves insulin action and glucose metabolism. After careful data analysis, the results will be evaluated and interpreted. Data will be presented at scientific meetings. Further, data will be disseminated through publications in leading journals in the field.

Progress 10/01/11 to 09/30/16

Outputs
OUTPUTS: Activities: The overall goals of this project were to characterize mechanisms by which curcumin exerts anti-obesity effects and improves insulin action and glucose metabolism. Curcumin has been shown to modulate a wide range of transcription factors, growth factors, inflammatory cytokines, and enzymes, including peroxisome proliferator-activiated receptor-γ, vascular endothelial growth factor, tumor necrosis factor α, cyclooxygenase-2 and AMP-activated protein kinase. However, whether curcumin is a ligand for PPARgamma is debatable. Two groups showed that curcumin is a PPARgamma ligand, and another group showed otherwise. Further, since the TZD class of antidiabetic drugs, including rosiglitazone and pioglitazone, potent activators of PPARgamma, have serious side effects such as fluid retention, weight gain, congesttive heart failure, and loss of bone mineral density in type 2 patients, identification of novel compounds or bioactive components that can selectively modulate PPARgamma activation and target gene expression may be of merit. Experiments were conducted to evaluate the ability of curcumin to modulate PPARgamma transcriptional activity, its target gene expression, and adipocyte differentiation in human subcutaneous adipocytes. Events: Findings from these studies were presented at the 11th Annual Diabetes and Obesity Conference: Strengthening Community Links to Address Diabetes and Obesity, organized by the Alabama Cooperative Extension System, Montgomery, AL, April 22-24. This talk was attended by over 200 delegates comprising healthcare workers, dietitians, nutritionists, community health education specialists, health policy makers, caregivers, medical researchers, social workers, and county agents working among people with obesity and diabetes, primarily within the state of Alabama. A few delegates from Georgia, and other states also attended the conference. Dissemination: A printout of the PowerPoint slides were made available to conference participants. PARTICIPANTS: Suresh Mathews: Served as PI on this project, and directed the molecular experiments that were conducted. PI was directly involved with the experimental design, experimentation, data analyses, and preparation of project reports. PI also directed the research of graduate student Jian (Albert)Zhang. Jian (Albert) Zhang: Lead graduate student for this project, was involved in characterizing curcumin's effects of PPARgamma activation. Partner organizations: PI collaborated with Sabinsa Corporation, that manufactures curcumin and tetrahydrocurcumin. These bioactive components were provided as gifts to the PI. TARGET AUDIENCES: Target groups included scientists, medical researchers, graduate students, healthcare workers, dietitians, nutritionists, community health education specialists, health policy makers, caregivers, social workers, and county agents working among people with obesity and diabetes. Efforts include classroom instruction (NTRI 8970 - Advanced Topics in Nutrition - Diabetes), laboratory instruction, conference presentation, extension and outreach efforts. PROJECT MODIFICATIONS: Nothing significant to report during this reporting period.

Impacts
Our studies demonstrate that curcumin and tetrahydrocurcumin induced a moderate increase in PPARgamma transcriptional activation (~20-fold increase compared to 90-fold increase with rosiglitazone). Interestingly, unlike rosiglitazone, troglitazone, and the natural ligand 15-deoxy-d 12,14 prostaglandin J2, curcumin or tetrahydrocurcumin did not induce differentiation of human subcutaneous adipocytes. Additionally, curcumin treatment decreased rosiglitazone-induced adipocyte differentiation, suggesting an uncoupling of effects and/or a differentially-induced receptor effect. Unlike rosiglitazone, curcumin moderately induced CD36 and adiponectin gene expression in differentiated 3T3-L1 adipocytes. Further, curcumin significantly increased adiponectin secretion compared to rosiglitazone, in 3T3-L1 adipocytes and differentiated sub-cutaneous human adipocytes. These data are suggestive of a potential role for the bioactive component, curcumin, to function as a selective PPARgamma modulator.

Publications

  • Mathews ST, Zhang, AJ, Kim T, Davis J. Molecular mechanisms mediating insulin-sensitizing effects of curcumin. Abstracted. AGFD Cornucopia Spring 2010, SA4, p.21, 2010. 239th American Chemical Society National Meeting, San Francisco, CA, 2010
  • Mathews ST. Medicinal plants and herbs in the management of diabetes. 11th Annual Diabetes and Obesity Conference: Strengthening Community Links to Address Diabetes and Obesity, Montgomery, April 22-24, 2012.
  • Zhang AJ. Ph.D Thesis. Mechanisms mediating antidiabetic effects of serviceberry extracts, curcumin, and stilbenes. Submitted to Auburn University (Major Professor: Suresh T. Mathews), May 7, 2012.
  • Zhang AJ, Kim T, Davis J, and Mathews ST. Curcumin enhances transcriptional activation of PPARg without inducing adipocyte differentiation. PPAR Research (manuscript in review, 2013).


Progress 01/01/11 to 12/31/11

Outputs
OUTPUTS: Activities: During the period under, studies to characterize the effects of curcumin on the nuclear receptor PPARgamma have been initialized. Additionally, PI has successfully solicited the collaboration of Sabinsa Corporation (East Windsor, NJ) that manufacture curcumin and tetrahydrocurcumin. Sabinsa Corporation has gifted the PI adequate amounts of curcumin and tetrahydro curcumin to initiate animal feeding studies. PI has also established contacts with Research Diets (New Brunswick, NJ) and discussed methodology related to incorporating formulations of curcumin into the diets of animals. PARTICIPANTS: Suresh Mathews: PI has been involved in obtaining adequate amounts of curcumin and tetrahydrocurcumin as gifts from Sabinsa Corporation (East Windsor, NJ). He has also discussed formulations of these compounds into animal diets,with Research Diets (New Brunswick, NJ). Dr. Mathews was involved with the experimental design, experimentation, and data analysis, and preparation of project reports. Jian Zhang: Graduate student, lead graduate student, has been involved in characterizing the mechanism of curcumin action related to PPARgamma activation. TARGET AUDIENCES: Target groups included scientists and researchers. Results from these studies were informally discussed among scientists and researchers at Auburn University, Sabinsa Corporation, and Research Diets. PROJECT MODIFICATIONS: Not relevant to this project.

Impacts
Results from the mechanistic studies related to PPARgamma activation by curcumin have demonstrated that curcumin acts as a partial modulator of PPARgamma transcriptional activation, and expression of its target genes. Curcumin and tetrahydrocurcumin increase the gene expression of adiponectin and its secretion from adipocytes.

Publications

  • No publications reported this period