The Rosmarinus Bioactive Compound Carnosic Acid Is a Novel PPAR Antagonist That Inhibits the Browning of White Adipocytes

Abstract

Thermogenic brown and brite adipocytes convert chemical energy from nutrients into heat. Therapeutics that regulate brown adipocyte recruitment and activity represent interesting strategies to control fat mass such as in obesity or cachexia. The peroxisome proliferator-activated receptor (PPAR) family plays key roles in the maintenance of adipose tissue and in the regulation of thermogenic activity. Activation of these receptors induce browning of white adipocyte. The purpose of this work was to characterize the role of carnosic acid (CA), a compound used in traditional medicine, in the control of brown/brite adipocyte formation and function. We used human multipotent adipose-derived stem (hMADS) cells differentiated into white or brite adipocytes. The expression of key marker genes was determined using RT-qPCR and western blotting. We show here that CA inhibits the browning of white adipocytes and favors decreased gene expression of thermogenic markers. CA treatment does not affect β-adrenergic response. Importantly, the effects of CA are fully reversible. We used transactivation assays to show that CA has a PPARα/γ antagonistic action. Our data pinpoint CA as a drug able to control PPAR activity through an antagonistic effect. These observations shed some light on the development of natural PPAR antagonists and their potential effects on thermogenic response.

Phenolic diterpenes from Rosemary supercritical extract inhibit non-small cell lung cancer lipid metabolism and synergise with therapeutic drugs in the clinic

“…Altered lipid metabolism has been found in many types of cancer and, consequently, lipid metabolism genes could constitute a prognostic and therapeutic tool in different tumours ( 31 ). Rosemary extracts has been described to inhibit relevant molecular pathways and transcription factors implicated in lipid metabolism ( 50 , 51 ).…”

Potential lipolytic regulators derived from natural products as effective approaches to treat obesity

“…AS-IV ( 131 ), curcumin ( 132 ), emodin ( 133 ), eicosapentaenoic acid (EPA) ( 134 ), and phillyrin ( 135 ) attenuates TNF-α-induced lipolysis by suppressing p-ERK1/2 and reversing perilipin or p-perilipin downregulation. Rosmarinic acid (RA) ( 136 , 137 ), RSV ( 116 ), BBR ( 83 ), cyanidin-3-O-β-glucoside (C3G) ( 138 ), dihydrodehydrodiisoeugenol (DDE) ( 139 ), carnosic acid ( 137 ), and piceatannol ( 140 ) may also inhibit lipolysis. The effects and mechanisms of these compounds are summarized in Table 5 .…”

Towards Drug Repurposing in Cancer Cachexia: Potential Targets and Candidates

“…PPARγ activation enhances UCP1 expression driving to BAT formation and regulating the thermogenic activity [101,102]. On the other hand, PPARγ antagonists inhibit the browning process and also decreas the expression of thermogenic key markers [103].…”

“…PPARγ Antagonist Diclofenac Diclofenac is a PPARγ antagonists that is already approved by the FDA [116]. PPARγ antagonists could be important to improve the cachexia treatment since they inhibit the browning process and also decrease the expression of thermogenic key markers [103]. The adverse symptoms are mostly skin reactions, loss of taste, and joint pain/swollenness [116].…”