Progress 09/01/09 to 02/28/13
Target Audience: Our research has been conducted in the interest of the scientific community in general and researchers in obesity research and food for health in particular. Changes/Problems:
What opportunities for training and professional development has the project provided?
How have the results been disseminated to communities of interest?
What do you plan to do during the next reporting period to accomplish the goals?
What was accomplished under these goals?
The intestine is the site for nutrient absorption and host defense through maintenance of the epithelial barrier, gut microbial balance, and host immunity. Recently, obesity is found to contribute to an increase in tight junction permeability, immunity and glucose absorption in intestine, resulting in an increase in the risk of intestinal diseases, such as inflammatory bowel disease and food-borne diseases, and hyperglycemia. These are likely due to elevated level of intestinal fatty acids and gastric leptin, an obesity-related hormone influencing on body weight management, and in intestine. Since curcumin has been shwon to be beneficial to prevent the development of obesity and obesity-related dysfunction. We tested the effect of curcumin on leptin-induced alteration of intestine function. We found that preexposure of human intestinal epithelial cells to curcumin protected cells from leptin-induced intestinal permeability and inflammation in vitro. This is through curcumin-inhibited leptin receptor singaling pathway in human intestinal epithelial cells.Since curcumin is safe and easily formulated within the food matrix, our study will ultimately help establish a practical dietary strategy to prevent obesity-associated impairment of functional homeostasis of intestine.
Kim, C.Y., and Kim, K.-H. (2013) "Curcumin prevents leptin-induced tight junction dysfunction in intestinal Caco-2 BBe cells" J. Nut. Biochem 25:26-35 (accepted for publication)
Progress 09/01/11 to 08/31/12
OUTPUTS: During this period, our research effort has been focused on determining the preventive function of curcumin in leptin-induced impairment of tight junction (TJ) in human epithelial enterocytes. Leptin's function in obesity is well-documented. However, the role of leptin in intestinal permeability is not known. Thus, we tested the effect of leptin on intestinal permeability and inflammation using Caco-2 human epithelial colorectal adenocarcinoma cells as an in vitro model of enterocytes. We found that leptin treatment to the apical side of polarized Caco-2 BBe cells caused TJ barrier dysfunction. TJ dysfunction by apical leptin was associated with reduced levels of genes encoding TJ-associated proteins, and elevated levels of pro-inflammatory genes. Moreover, apical leptin treatment resulted in activation of leptin signaling pathway, which appears to mediate leptin-impaired intestinal TJ function. We also observe a complete inhibition of leptin-induced tight junction permeability by curcumin pretreatment. Currently, we are attempting to elucidate molecular basis underlying curcumin-inhibited leptin-induced TJ impairment in human epithelial enterocytes. PARTICIPANTS: 1. PI: Kee-Hong Kim, 2. Choon Young Kim. TARGET AUDIENCES: Our research has been conducted in the interest of the scientific community in general and researchers in obesity research and food for health in particular. PROJECT MODIFICATIONS: Nothing significant to report during this reporting period.
Our results reveal previously unknown functions of luminal leptin and leptin signaling pathway in intestinal TJ function and identify luminal leptin as a potential modulator of intestinal dysfunction. Moreover, our results suggest that curcumin effectively protects leptin-induced functional defect in intestine, implicating new role of curcumin in promoting gut health.
- Kim, C.Y. Le, T. Chen, C.Y., Cheng, J.X., Kim, K.-H. 2011. Curcumin inhibits adipogenesis through suppression of mitotic clonal expansion. Journal of Nutritional Biochemistry. 22:910-920
- Kim, H., Amalaradjou, M.A.R., Kim, K.-H., Bhunia, A. 2012. Listeria Adhesion Protein Induces Epithelial Tight Junction Compromise through Activation of NF-kappaB and Down Regulation of Tight Junction Proteins. Annual Meeting of American Society for Microbiology, San Francisco, CA
- Kim, C.Y., Kim, K.-H. 2012. Luminal Leptin Impairs Intestinal Tight Junction Function in Vitro through JAK2-Dependent Signaling Pathway. Experimental Biology Annual Meeting, San Diego, CA
Progress 09/01/10 to 08/31/11
OUTPUTS: To date we have determined the anti-adipogenic function of curcumin and its underlying mechanism as proposed in the Objective 1. Despite its health benefit, poor solubility and bioavailability of curcumin limits its practical usage in the physiological condition. During this period we further developed a water-soluble curcumin and examined its bioavailability and improved anti-adipogenic property in preadipocytes. This is through collaboration with Ahamd Safavy of University of Alabama, and Mario Ferruzzi and Ji-Xin Cheng of Purdue University. We observed that the water-soluble curcumin generated through conjugation with polyethylene glycol (PEG) was rapidly absorbed to preadipocytes with extended stability in the cell compared with natural form of curcumin. We also attempted to determine and compare the different absorption kinetics between these two forms of curcumin in preadipocytes. This improved water solubility and bioavailability of curcumin by conjugation with PEG was associated with enhanced anti-adipogenic effect of curcumin during the differentiation of preadipocytes. In this period we also attempted to elucidate the anti-inflammatory function of curcumin in obesity and its related physiological disorders. We currently test the protective function of curcumin in adipokine-induced intestinal dysfunction. PARTICIPANTS: 1. PI: Kee-Hong Kim, 2. Choon Young Kim. 3. Nicolas Bordenave. 4. Mario Ferruzzi. 5. Ahmad Safavy. 6. Tuc Le. 7. Ji-Xin Cheng. 8. Yeonhwa Park TARGET AUDIENCES: Our research has been conducted in the interest of the scientific community in general and researchers in obesity research and food for health in particular. PROJECT MODIFICATIONS: Nothing significant to report during this reporting period.
While curcumin intake at high dose is still safe in humans, its poor bioavailability and rapid degradation/metabolism in the body are the main hurdles in dietary prevention of obesity using curcumin. Although more studies are needed to verify the bioavailability of PEG-conjugated curcumin in vivo, our current finding indicates that PEGylation-improved water solubility and cellular retention of curcumin may be uniquely useful for improving the bioavailability of curcumin in preadipocytes and its anti-adipogenic ability.
- 1. Kim CY, Bordenave N, Ferruzzi MG, Safavy A, Kim KH. (2011) Modification of curcumin with polyethylene glycol enhances the delivery of curcumin in preadipocytes and its antiadipogenic property. J Agric Food Chem. 59:1012-9.
- 2. Kim CY, Le TT, Chen C, Cheng JX, Kim KH. (2011) Curcumin inhibits adipocyte differentiation through modulation of mitotic clonal expansion. J Nutr Biochem. 22:910-20.
- 3. Kim KH, Park Y.(2011) Food components with anti-obesity effect. Annu. Rev. Food Sci. Technol. 2:237-57
- 4. Kim, K.H. (2010) Anti-obese function of curcumin, Annual Showalter Trustee Visit, Purdue University.
- 5. Kim, K.H., Kim, C.Y., Bordenave, N., Ferruzzi, M.G.. Safavy, A. (2011) Improved bioavailability and anti-adipogenic property of water-soluble curcumin conjugates. Experimental Biology Annual Meeting, Washington D.C.
Progress 09/01/09 to 08/31/10
OUTPUTS: We completed all the experiments proposed in the Objective 1. In collaboration with Ji-xin Cheng of Purdue University, the principal research outputs obtained during this period were (i) elucidation of the anti-adipogenic function of curcumin and its mode of action in vitro, ii) developing a novel non-invasive imaging technique of for visualization of lipid droplet formation and accumulation of intracellular curcumin in adipocytes during adipogenesis, and iii) establishment of a biochemical approach to be used to examine the anti-inflammatory property of curcumin in differentiated adipocytes. We demonstrated that curcumin exerts an anti-adipogenic function both in murine and human primary preadipocytes as determined by intracellular lipid accumulation assay and quantitative analysis of adipocyte marker gene expression. The inhibitory action of curcumin was largely limited to the early stage of adipocyte differentiation, where curcumin is able to inhibit mitotic clonal expansion (MCE) process of differentiating preadipocytes with no significant effect on cell viability and cytotoxicity. A non-invasive multimodal Coherent Anti-Stokes Raman Scattering (CARS) microscopic analysis revealed a rapid uptake and degradation of intracellular curcumin during the early stage of adipogenesis, which is correlated with its anti-adipogenic property. We also found that the anti-adipogenic function of curcumin is likely to be mediated through suppression of the mRNA levels of key adipogenic transcription factors, such as CCAAT/enhancer binding protein alpha (C/EBPalpha) and peroxisome proliferator-activated receptor gamma (PPARgamma) during the early stage of adipogenesis. Taken together, we demonstrated that curcumin is an anti-adipogenic dietary bioactive component largely involved in the modulation of the cellular and transcriptional programs in the MCE process during the early stage of adipogenesis. PARTICIPANTS: 1. PI: Kee-Hong Kim, 2. Choon Young Kim. 3. Julie Wiacek, 4: Allison Martorano TARGET AUDIENCES: Our research has been conducted in the interest of the scientific community in general and researchers in obesity research and food for health in particular. PROJECT MODIFICATIONS: Nothing significant to report during this reporting period.
Curcumin has recently been proposed to be a potential anti-obesity dietary component. However, its efficacy and effective dosage in preventing the development of obesity in animals is varying depending on the study designs and the obesity status of experimental animals. Understanding of how curcumin modulates the biochemical and molecular events in adipose tissue development during the course of obesity would provide potential opportunities for an effective way for the dietary prevention of obesity by curcumin. Thus far we have elucidated molecular basis underlying curcumin-inhibited adipogenesis. Our results suggest that curcumin effectively controls the molecular and cellular programs required for the initiation of the early processes in the conversion of preadipocytes to differentiating adipocytes.
- Kim, CY, Le T, Chen, CY, Cheng, JX and Kim, KH. 2010. Curcumin Inhibits Adipocyte Differentiation through Modulation of Mitotic Clonal Expansion. Journal of Nutritional Biochemistry (in press)
- Kim, KH. 2009. Perspective in Regulation of Adipogenesis by Bioactive Food Components. Food Science and Industry, 42(4): 51-57
- Kim, KH. 2010. Dietary Regulation of Adipose Development: Role of Curcumin in Adipogenesis. Annual Meeting of the Korean Society of Food Science & Technology 2010 (June, 2010), Incheon, Korea