Carnosic Acid and Carnosol, Phenolic Diterpene Compounds of the Labiate Herbs Rosemary and Sage, are Activators of the Human Peroxisome Proliferator-Activated Receptor Gamma

Abstract

Peroxisome proliferator-activated receptor gamma (PPARgamma) is a ligand activated transcription factor, belonging to the metazoan family of nuclear hormone receptors. Activation of PPARgamma increases the transcription of enzymes involved in primary metabolism, leading to lower blood levels of fatty acids and glucose. Hence, PPARgamma represents the major target for the glitazone type of drugs currently being used clinically for the treatment of type 2 diabetes. Furthermore, activators of PPARgamma show beneficial anti-inflammatory and anti-tumour effects. Utilizing a fusion receptor of the yeast Gal4-DNA binding domain joined to the hinge region and ligand binding domain of the human PPARgamma in combination with a Gal4-driven luciferase reporter gene, cotransfected into Cos7 cells, we tested sage and rosemary extracts prepared with 80 % aqueous ethanol for possible PPARgamma activation. This revealed that both extracts are capable of selectively activating Gal4-PPARgamma fusion receptor, in a concentration-dependent manner, with EC (50) values of 22.8 +/- 8.4 mg/L and 33.7 +/- 7.3 mg/L for rosemary and sage, respectively. Subsequent analysis of the characteristic constituents revealed the phenolic diterpene compounds carnosol, present in both herbs, and carnosic acid to be active principles of these extracts, showing EC (50) values of 41.2 +/- 5.9 microM and 19.6 +/- 2.0 microM, respectively. Thus it can be concluded that the glucose lowering effect reported recently for rosemary may be attributed to PPARgamma activation. Moreover, our observations may also explain the anti-inflammatory and antiproliferative effects of both compounds published previously.

Carnosic acid, an inducer of NAD(P)H quinone oxidoreductase 1, enhances the cytotoxicity of β‑lapachone in melanoma cell lines

“…CA has various biological effects, mediated via phosphatidylinositol 3-kinase (39), peroxisome proliferator-activated receptor γ (40), cyclin A/B1 (41) and free radical-scavenging activity (42). CA is also known to activate the KEAP1/NRF2 system (23).…”

Biopartitioning micellar chromatography to predict blood to lung, blood to liver, blood to fat and blood to skin partition coefficients of drugs

“…In in vitro trials, carnosic acid inhibits pancreatic lipase (19) , activates PPAR-g (20) and prevents the differentiation of mouse pre-adipocytes into adipocytes (21) -all of which are important mechanisms in glucose and lipid homeostasis. The capacity of rosemary to regulate weight gain (22,23) and glycaemia (22 -24) has been observed in vivo.…”

Obtention and Characterization of Rosemary and Ash Tree Seed Extracts and Study of Their Preventive Effects on Metabolic Disorders

“…Rosemary exerts various biological activities with which preventive nutritional strategies against metabolic disorders, such as obesity, dyslipidaemia, and diabetes, can be developed (Ninomiya et al, 2004;Rau et al, 2006;Takahashi et al, 2009;Harach et al, 2010;Wang et al, 2011). Nevertheless, individual studies have examined specific extracts, the chemical description of which is not always available.…”

“…Recently, rosemary extracts that have been standardized for carnosic acid and carnosol have attained antioxidant status, garneging an E rating from the European Food Safety Authority, confirming its importance as a natural preservative in foods and beverages . Rosemary has many health benefits (al-Sereiti et al, 1999), and its effects on oxidative stress (Etter, 2004), inflammation (Takaki et al, 2008;Altinier et al, 2007); obesity (Takahashi et al, 2009;Harach et al, 2009), and diabetes Rau et al, 2006) are central to the prevention of metabolic disorders.…”

“…In in vitro trials, carnosic acid inhibits pancreatic lipase (Ninomiya et al, 2004), activates peroxisome proliferators-activated receptor gamma (PPARγ) (Rau et al, 2006), and prevents the differentiation of mouse pre-adipocytes into adipocytes (Takahashi et al, 2009) -all of which are important mechanisms in glucose and lipid homeostasis. The capacity of rosemary to regulate weight gain (Harach et al, 2010;Wang et al, 2011) and glycaemia (Erenmemisoglu et al, 1997;Harach et al, 2010;Wang et al, 2011) has been observed in vivo.…”