How fenofibrate and endocannabinoids crosstalk through PPAR
Updated: Feb 8
Cutting weight without eating less is almost tied to a modern rendition of the American Dream. But two nonessential fats can do this, to an extent, by targeting a receptor. They are unique fatty acids that target a receptor that breaks down other fatty acids. A recent study further mapped out how Fenofibrate crosstalks with endocannabinoids by chronically agonizing the receptor, which is known as a PPAR.
Fenofibrate is a drug that targets abnormal levels of blood-borne lipids by activating PPAR-alpha, more specifically. The University of Cagliari and Anna Lisa Muntoni’s Lab of the National Research Council of Italy funded the latest paper on the drug’s relationship with the endocannabinoid system. The mice in the study lost weight relatively more than they stopped eating, a phenomenon known as reduced feed efficiency. (1)
PPARs in the Endocannabinoidome
A system found in the 1990s interacts with cannabis’s intoxicating ingredient, THC. By 1995, researchers named this system our endocannabinoid system (ECS) and it comprises two primary receptors and endocannabinoids. A larger network known as the endocannabinoidome does, however, consist of numerous components.
We know of three Peroxisome Proliferating Activated Receptors (PPARs) — alpha, delta, and gamma. (2) The superfamily was first spotted in 1990 and characterized by 1993. (3, 4) That same year, Rita Levi-Montalcini researched mast cells and Palmitoylethanolamide (PEA). (5)
PPARs regulate many functions, including genes. As their name implies, though, they especially encourage more lipid oxidization. And in reverse, fatty acids activate PPARs, which means they interact back and forth. Adding to this, endocannabinoids are a type of fatty acid. Inspired by Levi-Montalcini, a team of scientists looked for PEA’s binding site in two studies in 2005 and found out that it targets the peroxidizing receptor, PPAR-alpha. (6, 7)
Anandamide, 2-AG, and PPAR agonists
Researchers dosed the diets of lab mice with 0.2% Fenofibrate, a PPAR-alpha agonist. Lab mice in the study lost 9% bodyweight after seven days and 19% after 19 days. Compared to their weight loss, though, their food consumption only dropped 10.5% after receiving a medicated diet for 21 days.
They tested the rodent’s adipose (fatty) tissue and their liver, an area dense with PPAR-alpha. The dose given to mice ultimately oxidizes Omega-3 fats. And since Omega-3s metabolize into endocannabinoids, Fenofibrate reduced anandamide tone in the liver. In fatty tissue, though, the drug boosted anandamide levels by a small percentage. But another mechanism might work against endocannabinoids in the feedback loop.
The PPAR-alpha agonist boosted PEA and OEA levels in the liver, which the researchers suggest can compete with anandamide. They suggested that,
“Since it has been shown that the biosynthesis of these lipid mediators may be modulated by dietary [fatty acids], particularly [omega 3]-PUFA, future studies should evaluate whether [Omega 3]-HUFA supplementation can further modulate the biosynthesis of eCB and eCB-like molecules, restoring their tissue levels.”
Fenofibrate and endocannabinoid metabolism
PPAR agonists induce functions that either engage with the metabolism of endocannabinoids or their respective receptors. Fenofibrate agonizes PPAR-alpha, which oxidizes fatty acids, but the drug also binds to the CB2 receptor in the ECS. And more than this, the drug can activate the CB1 receptor in low doses, whereas acute doses are not much more potent.
In fact, CBD shares similar functions at these two cannabinoid receptors as Fenofibrate. We cannot, however, compare the drug and the cannabinoid at PPARs. An agonist’s shape impacts how it binds to a receptor, which can alter its function. For example, PEA is relatively safe, only causing nausea and heaviness in the stomach. Whereas Fenofibrate’s adverse reactions include liver damage, loss of appetite, nausea, vomiting, and abdominal pain. (1)
Studies continue to find deeper meaning in the relationship between PPARs and fatty acids. (8, 9) More results are, however, required to fully map how Fenofibrate and the endocannabinoid system crosstalk.
Murru E, Muntoni AL, Manca C, Aroni S, Pistis M, Banni S, Carta G. Profound Modification of Fatty Acid Profile and Endocannabinoid-Related Mediators in PPARα Agonist Fenofibrate-Treated Mice. International Journal of Molecular Sciences. 2023; 24(1):709
Wagner N, Wagner KD. PPAR Beta/Delta and the Hallmarks of Cancer. Cells. 2020;9(5):1133. Published 2020 May 4. doi:10.3390/cells9051133
Issemann I, Green S (1990) Activation of a member of the steroid hormone receptor superfamily by peroxisome proliferators. Nature 347, 645-650
Dreyer, Christine; Keller, Hansjög; Mahfoudi, Abderrahim; Laudet, Vincent; Krey, Grigorios; Wahli, Walter (1993). Positive regulation of the peroxisomal β-oxidation pathway by fatty acids through activation of peroxisome proliferator-activated receptors (PPAR). Biology of the Cell, 77(1), 67–74. doi:10.1016/S0248-4900(05)80176-5
Aloe L, Leon A, Levi-Montalcini R. A proposed autacoid mechanism controlling mastocyte behaviour. Agents Actions 1993;39:C145–7.
LoVerme J, La Rana G, Russo R, Calignano A, Piomelli D. The search for the palmitoylethanolamide receptor. Life Sci 2005;19(77):1685–98. 26.
Lo Verme J, Fu J, Astarita G, La Rana G, Russo R, Calignano A, et al. The nuclear receptor peroxisome proliferator-activated receptor- alpha mediates the anti-inflammatory actions of palmitoylethanolamide. Mol Pharmacol 2005;67:15–9.
Törüner F, Akbay E, Cakir N, et al. Effects of PPARgamma and PPARalpha agonists on serum leptin levels in diet-induced obese rats. Horm Metab Res. 2004;36(4):226-230. doi:10.1055/s-2004-814452
Gasperi V, Fezza F, Spagnuolo P, Pasquariello N, Maccarrone M. Further insights into the regulation of human FAAH by progesterone and leptin implications for endogenous levels of anandamide and apoptosis of immune and neuronal cells. Neurotoxicology. 2005;26(5):811-817. doi:10.1016/j.neuro.2005.08.002