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Project 1: Botanicals and Metabolic Flexibility Return to Projects

In the initial funding cycle (2005-2010) for our Botanical Research Center, Project 1 investigators provided definitive evidence that a well characterized extract of Artemisia dracunculus L. (PMI5011) regulated insulin receptor signaling at the cellular level, increased insulin sensitivity in vivo, and identified novel proteins and several intracellular pathways modulated by the extract (1-8). For the 2nd funding cycle (2010-2015), we expanded in two major areas: identified other promising botanical leads (i.e., bitter melon and other members of the Artemisia genus) and used state-of-the-art metabolomic and proteomic techniques, combined with cellular signaling approaches to provide a comprehensive analysis of the mechanisms of action by which botanicals improve insulin sensitivity and carbohydrate metabolism (9-17). Our efforts have clearly advanced the field and led to ongoing clinical testing of PMI5011. Our investigations yielded significant insight into the “triggers” of disease state development and we are now poised to take the logical next steps and evaluate the relationship between botanically-mediated enhanced insulin sensitivity and metabolic resiliency to the adverse tissue and whole body impact of exposure to an obesogenic environment.

Our specific aims were:

Aim 1: To test the hypothesis that mechanisms by which Artemisia sp. extracts improve insulin action in vivo include modulation of lipid metabolism and reduction of intramuscular and intrahepatic lipids

Aim 2: To test the hypothesis that extracts from Artemisia sp. modulate skeletal muscle protein tyrosine phosphatase (PTPase) levels and activity and enhance phosphorylation of intracellular substrates of the insulin signaling cascade

Aim 3: To evaluate the effect of bioactive components of Artemisia sp. in vivo on insulin sensitivity in human subjects and on cellular pathways regulating insulin signaling.

 Overview of Major Findings

We have reported favorable effects of Artemisia sp. extracts to attenuate reduced insulin action in muscle secondary to lipid intermediates and evaluated effects on lipid production. We have reported on favorable effects of Artemisia sp. extracts to modulate hepatic cellular signaling and to reduce hepatic lipids and identified specific bioactives (i.e., DMC-2) that mediate the effects of A. dracunculus. We have demonstrated efficacy of Artemisia sp. to reduce PTP1B content and activities in liver and muscle and completed bioinformatics analyses that reported metabolic pathways related to glucose metabolism and cell signaling in response to A. dracunculus. We have reported phosphoproteomics analysis demonstrating that PMI5011 effects changes in protein phosphorylation levels and identified novel pathways by which it exerts its insulin sensitizing effects in skeletal muscle. Finally, in collaboration with Botanical Core, we evaluated PMI5011 formulation in pre-clinical studies for clinical evaluation (15).

 Current Direction

For our next steps in evaluation, the objective will be to test the general hypothesis that the selected botanicals promote metabolic resiliency to “metabolic dysfunction” (i.e., insulin resistance, glucose intolerance, obesity) by regulating whole body substrate metabolism, skeletal muscle protein metabolism, and botanical-gene interactions in insulin responsive peripheral tissues as indicators of “metabolic flexibility”. As part of our proposed direction, we will also assess potential gender differences in the effect of the selected botanicals on muscle function with aging, an area of great public health concern and one for which there is a paucity of data.

Aim 1: To test the hypothesis that bitter melon and Artemisia dracunculus L. promote resilience to an obesogenic environment by regulating the capacity to switch from carbohydrate to lipid oxidation in response to high fat diets (a measure of “metabolic flexibility”).  

Aim 2: To test the hypothesis that maintenance of metabolic flexibility by bitter melon and A. dracunculus in an obesogenic environment is secondary to regulation of PGC-1-mediated gene expression across insulin responsive peripheral tissues.

Aim 3: To test the hypothesis that maintenance of normal skeletal muscle structure and function via regulation of ubiquitin-proteasome protein degradation is a major contributing mechanism by which botanicals regulates metabolic flexibility in the presence of an obesogenic environment during aging.

 

References

 

  1. Wang ZQ, Ribnicky D, Zhang XH, Raskin I, Yu Y, Cefalu WT. Bioactives of Artemisia dracunculus L enhance cellular insulin signaling in primary human skeletal muscle culture. Metabolism 2008;57:S58-S6.
  2. Ribnicky DM, Poulev A, Watford M, Cefalu WT, Raskin I. Antihyperglycemic activity of Tarralin, an ethanolic extract of Artemisia dracunculus L. Phytomedicine 2006;13:550-555.
  3. Kheterpal I, Coleman L, Ku G, Wang ZQ, Ribnicky D, Cefalu WT. Regulation of insulin action by an extract of Artemisia dracunculus L. in primary human skeletal muscle culture: A proteomics approach. Phytother Res 2010 Sep;24(9):1278-1284.
  4. Wang ZQ, Ribnicky D, Zhang XH, Zuberi A, Raskin I, Yu Y, Cefalu WT. An extract of Artemisia dracunculus L. enhances insulin receptor signaling and modulates gene expression in skeletal muscle in KK-A(y) mice. J Nutr Biochem 2011;22:71-78.
  5. Logendra S, Ribnicky DM, Yang H, Poulev A, Ma J, Kennelly EJ, Raskin I. Bioassay-guided isolation of aldose reductase inhibitors from Artemisia dracunculus. Phytochemistry 2006;67:1539-1546.
  6. Ribnicky DM, Kuhn P, Poulev A, Logendra S, Zuberi A, Cefalu WT, Raskin I. Improved absorption and bioactivity of active compounds from an anti-diabetic extract of Artemisia dracunculus L. Int J Pharm 2009;370:87-92.
  7. Govorko D, Logendra S, Wang Y, Esposito D, Komarnytsky S, Ribnicky D, Poulev A, Wang Z, Cefalu WT, Raskin I. Polyphenolic compounds from Artemisia dracunculus L. inhibit PEPCK gene expression and gluconeogenesis in an H4IIE hepatoma cell line. Am J Physiol Endocrinol Metab 2007;293:E1503-E1510.
  8. Schmidt B, Ribnicky DM, Poulev A, Logendra S, Cefalu WT, Raskin I. A natural history of botanical therapeutics. Metabolism 2008;57:S3-S9.
  9. Obanda DN, Hernandez A, Ribnicky D, Yu Y, Zhang XH, Wang ZQ, Cefalu WT. Bioactives of Artemisia dracunculus L. mitigate the role of ceramides in attenuating insulin signaling in rat skeletal muscle cells. Diabetes 2012;61:597-605.
  10. Rood JS, Schwarz J-M, Gettys, TW, Mynatt RL, Mendoza T, Johnson WD, Cefalu WT. Effects of Artemisia species on de novo lipogenesis in vivo. Nutrition 2014;30(7-8):S17-S20.
  11. Wang ZQ, Zhang XH, Yu Y, Tipton RC, Raskin I, Ribnicky D, Johnson W, Cefalu WT. Artemisia scoparia extract attenuates non-alcoholic fatty liver disease in diet-induced obesity mice by enhancing hepatic insulin and AMPK signaling independently of FGF21 pathway. Metabolism 2013 Sep;62(9):1239-1249.
  12. Obanda DN, Ribnicky DM, Raskin I, Cefalu WT. Bioactives of Artemisia dracunculus L. enhance insulin sensitivity by modulation of ceramide metabolism in rat skeletal muscle cells. Nutrition 2014;30(7-8)S59-S66.
  13. Scherp P, Putluri N, LeBlanc GJ, Wang ZQ, Zhang XH, Yu Y, Ribnicky D, Cefalu WT, Kheterpal I. Proteomic analysis reveals cellular pathways regulating carbohydrate metabolism that are modulated in primary human skeletal muscle culture due to treatment with bioactives from Artemisia dracunculus L. J Proteomics 2012 Jun 18;75(11):3199-3210.
  14. Kheterpal I, Scherp P, Kelley L, Wang Z, Johnson W, Ribnicky D, Cefalu WT. Bioactives from Artemisia dracunculus L. enhance insulin sensitivity via modulation of skeletal muscle protein phosphorylation. Nutrition 2014;30(7-8):S43-S51.
  15. Ribnicky DM, Roopchand DE, Poulev A, Kuhn P, Oren A, Cefalu WT, Raskin I. Artemisia dracunculus L. polyphenols complexed to soy protein show enhanced bioavailability and hypoglycemic activity in C57BL/6 mice. Nutrition 2014;30(7-8):S4-S10.
  16. Wang ZQ, Zhang XH, Yu Y, Poulev A, Ribnicky D, Floyd ZE, Cefalu WT. Bioactives from bitter melon enhance insulin signaling and modulate acyl carnitine content in skeletal muscle in high-fat diet-fed mice. J Nutr Biochem 2011 Nov;22(11):1064-1073.
  17.  Yu Y, Zhang XH, Ebersole B, Ribnicky D, Wang ZQ. Bitter melon extract attenuating hepatic steatosis may be mediated by FGF21 and AMPK/Sirt1 signaling in mice. Sci Rep 2013 Nov 5;3:3142.
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