Natural product agonists of peroxisomeproliferator-activated receptor gamma

(PPARγ): a review

Dr. Birgit Waltenberger

Institute of Pharmacy/Pharmacognosy &

Center for Molecular Biosciences Innsbruck (CMBI)

University of Innsbruck, Austria

Natural product agonists of PPARγ: a review. Limei Wang†, Birgit Waltenberger†, Eva-Maria Pferschy-Wenzig, MartinaBlunder, Xin Liu, Clemens Malainer, Tina Blazevic, Stefan Schwaiger, Judith M. Rollinger, Elke H. Heiss, Daniela Schuster,Brigitte Kopp, Rudolf Bauer, Hermann Stuppner, Verena M. Dirsch, Atanas G. Atanasov*. Biochemical Pharmacology, 2014

http://www.ncbi.nlm.nih.gov/pubmed/25083916

Significance of metabolic disorders

The metabolic syndrome:

• Abdominal obesity, hypertension, dyslipidemia, insulin resistance and

glucose intolerance, pro-thrombotic and pro-inflammatory states

Natural product agonists of PPARγ: a review. L. Wang, B. Waltenberger, et al., Biochemical Pharmacology, 2014

Significance of metabolic disorders

The metabolic syndrome:

• Abdominal obesity, hypertension, dyslipidemia, insulin resistance and

glucose intolerance, pro-thrombotic and pro-inflammatory states

• Greater risk of developing cardiovascular diseases and type 2 diabetes

Natural product agonists of PPARγ: a review. L. Wang, B. Waltenberger, et al., Biochemical Pharmacology, 2014

Significance of metabolic disorders

The metabolic syndrome:

• Abdominal obesity, hypertension, dyslipidemia, insulin resistance and

glucose intolerance, pro-thrombotic and pro-inflammatory states

• Greater risk of developing cardiovascular diseases and type 2 diabetes

• Affects more than a quarter of the world’s adult population

Natural product agonists of PPARγ: a review. L. Wang, B. Waltenberger, et al., Biochemical Pharmacology, 2014

Significance of metabolic disorders

The metabolic syndrome:

• Abdominal obesity, hypertension, dyslipidemia, insulin resistance and

glucose intolerance, pro-thrombotic and pro-inflammatory states

• Greater risk of developing cardiovascular diseases and type 2 diabetes

• Affects more than a quarter of the world’s adult population

• Contributes to mortality and morbidity worldwide

Natural product agonists of PPARγ: a review. L. Wang, B. Waltenberger, et al., Biochemical Pharmacology, 2014

Significance of metabolic disorders

Natural product agonists of PPARγ: a review. L. Wang, B. Waltenberger, et al., Biochemical Pharmacology, 2014

Metabolic syndrome management:

1. Life style modifications

2. Pharmaceutical drugs

Significance of metabolic disorders

Natural product agonists of PPARγ: a review. L. Wang, B. Waltenberger, et al., Biochemical Pharmacology, 2014

Pharmaceutical treatment of patients with type-2 diabetes:

• Insulin and insulin analogs

• Oral anti-hyperglycemic pharmaceuticals

Metabolic syndrome management:

1. Life style modifications

2. Pharmaceutical drugs

Significance of metabolic disorders

Natural product agonists of PPARγ: a review. L. Wang, B. Waltenberger, et al., Biochemical Pharmacology, 2014

Oral anti-hyperglycemicpharmaceuticals

Sulfonylureas↑ insulin secretion

Biguanidesinsulin

sensitizers

Thiazolidinedionesagonists of PPARγ

DPP-4 inhibitors ↑ insulin secretion

Meglitinides↑ insulin secretion

Alpha-glucosidase inhibitors slowing the digestion of

starch in the small intestine

PPARγ and the metabolic regulation

Natural product agonists of PPARγ: a review. L. Wang, B. Waltenberger, et al., Biochemical Pharmacology, 2014

PPAR

ligand

PPRE

Cell nucleus

Gene expression

changes

DNA

RXR

ligandTranscriptional

cofactors

21 3

RXRPPAR

PPARγ - nuclear receptor & ligand-inducible transcription factor

PPARγ and the metabolic regulation

Natural product agonists of PPARγ: a review. L. Wang, B. Waltenberger, et al., Biochemical Pharmacology, 2014

PPARγ activities in the human body:

• Adipocyte differentiation

• Lipid metabolism and glucose homeostasis

• Metabolism and inflammation in immune cells

• Cell proliferation

PPARγ and the metabolic regulation

Natural product agonists of PPARγ: a review. L. Wang, B. Waltenberger, et al., Biochemical Pharmacology, 2014

PPARγ activities in the human body:

• Adipocyte differentiation

• Lipid metabolism and glucose homeostasis

• Metabolism and inflammation in immune cells

• Cell proliferation

Endogenous ligands of PPARγ: Fatty acids & prostanoids (weak agonists)

Synthetic thiazolidinediones (full agonists): Troglitazone, rosiglitazone,

pioglitazone… Side effects: Hepatotoxicity, body-weight gain, risk of

myocardial infarction, heart failure & cardiovascular mortality, etc.

PPARγ activation by natural products

Natural product agonists of PPARγ: a review. L. Wang, B. Waltenberger, et al., Biochemical Pharmacology, 2014

Bixa orellana

Cannabis sativaSambucus nigraTrifolium pratense

Glycine max

Camellia sinensis

Origanum vulgare

Rosmarinus officinalis

Salvia officinalis

Thymus vulgaris

Vitis vinifera

PPARγ activation by natural products

Natural product agonists of PPARγ: a review. L. Wang, B. Waltenberger, et al., Biochemical Pharmacology, 2014

PPARγ activation by natural products

Natural product agonists of PPARγ: a review. L. Wang, B. Waltenberger, et al., Biochemical Pharmacology, 2014

Amorfrutin B

(PDB 4a4w)

Magnolol

(PDB 3r5n)

Luteolin

(PDB 3sz1)

Concluding remarks

Natural product agonists of PPARγ: a review. L. Wang, B. Waltenberger, et al., Biochemical Pharmacology, 2014

• Natural products are a rich source for PPARγ ligands

Concluding remarks

Natural product agonists of PPARγ: a review. L. Wang, B. Waltenberger, et al., Biochemical Pharmacology, 2014

• Natural products are a rich source for PPARγ ligands

• Many agonists identified from traditional medicinal plants or food sources

Concluding remarks

Natural product agonists of PPARγ: a review. L. Wang, B. Waltenberger, et al., Biochemical Pharmacology, 2014

• Natural products are a rich source for PPARγ ligands

• Many agonists identified from traditional medicinal plants or food sources

• Mostly weak agonists of PPARγ activ. pattern similar to endog. agonists

Concluding remarks

Natural product agonists of PPARγ: a review. L. Wang, B. Waltenberger, et al., Biochemical Pharmacology, 2014

• Natural products are a rich source for PPARγ ligands

• Many agonists identified from traditional medicinal plants or food sources

• Mostly weak agonists of PPARγ activ. pattern similar to endog. agonists

• Several agonists identified in plants used as culinary herbs, beverages or

food sources possibility to consider dietary interventions

Concluding remarks

Natural product agonists of PPARγ: a review. L. Wang, B. Waltenberger, et al., Biochemical Pharmacology, 2014

• Natural products are a rich source for PPARγ ligands

• Many agonists identified from traditional medicinal plants or food sources

• Mostly weak agonists of PPARγ activ. pattern similar to endog. agonists

• Several agonists identified in plants used as culinary herbs, beverages or

food sources possibility to consider dietary interventions

• PPARγ activating natural products & plant extracts = good potential for

further investigation for therapeutic effects & as potential dietary

supplements against metabolic syndrome and type 2 diabetes