Turning Up the Heat on Weight Loss

Indian restaurants are tricky for me because the spice level varies from place to place. A Spice Level 2 might be mild at one restaurant and near inedibly hot at another. What I do is order a milder meal and add hot chili oil to taste, but you can also reduce the heat! Some Indian restaurants will gladly add yogurt, sugar, or cashew paste to lower the spice level. This is strikingly similar to how receptors, some of the most important and widespread mechanisms in our bodies, function.

Receptors are proteins in the body that interact with a ligand. Ligands are typically molecules or proteins. When a ligand attaches to a receptor, the receptor makes a change to the cell it’s attached to.^[1] These changes can range from letting extra salt into the cell to mounting a defense response (if the ligand is part of a bacterium, for instance). The same receptors can produce different effects in different parts of the body, depending on what they are attached to.^[1] This makes sense: a receptor in the gut might interact with some tasty Indian food and tell the intestines to absorb the nutrients, but if a receptor detects tikka masala in your muscles, you want to get that out of there ASAP.

Having the same receptor in different places is smart thinking by the body, but it can pose real problems when it comes to medicine. Let’s look at the Cannabinoid 1 (CB1) receptor. This receptor activates spontaneously at low levels, like a Spice Level 2. Some ligands in the body (and some illicit drugs) activate this receptor and turn it up to a Spice Level 5. This has effects throughout the body and brain, including raising hunger (the munchies) and reducing energy expenditure, leading to lethargy. In the mid 2000s, the medicine rimonabant was approved overseas as a miracle weight loss drug.^[2] Rimonabant was a CB1 reverse agonist, meaning it was like adding yogurt to the spice, reducing it to a Spice Level 0 or 1.^[1,2]  In the body, the medication acts on the liver, skeletal muscle, fat tissue, and hormone systems.^[3] This gave marked improvements with energy balance, body weight, heart issues, and markers of diabetes.^[2,3] Unfortunately, rimonabant also binds to receptors in the brain, causing psychiatric side effects including worsening anxiety and depression, and rare suicidal ideation.^[2] The medicine was pulled from overseas markets after only a couple years and was never approved in the US.

The story of rimonabant isn’t a rare one, and researchers suspect that most unwanted side effects from medications come from the medication interacting with off-target receptors.^[1] What made rimonabant special is that there may be a way to reduce the psychological effects while continuing to get the benefits of weight loss and metabolic health.^[3] The goal of clinical researchers now is to develop medications that target CB1 receptors in the liver, muscles, and fat without affecting receptors in the brain.^[3] Luckily, there is a special barrier to the brain called the blood-brain barrier that prevents large molecules (including viruses and bacteria) from entering the brain and wreaking havoc.^[2] If scientists can develop a medication that can’t pass this barrier, they may be able to deliver weight loss medication with the perfect spice level for everyone.

Creative Director Benton Lowey-Ball, MWC, BS, BFA

References:

[1] Berg KA, Clarke WP. Making sense of pharmacology: inverse agonism and functional selectivity. International Journal of Neuropsychopharmacology. 2018 Oct;21(10):962-77. https://doi.org/10.1093/ijnp/pyy071

[2] Crater GD, Lalonde K, Ravenelle F, Harvey M, Després JP. Effects of CB1R inverse agonist, INV‐202, in patients with features of metabolic syndrome. A randomized, placebo‐controlled, double‐blind phase 1b study. Diabetes, Obesity and Metabolism. 2024 Feb;26(2):642-9. https://doi.org/10.1111/dom.15353

[3] Cinar R, Iyer MR, Kunos G. The therapeutic potential of second and third generation CB1R antagonists. Pharmacology & therapeutics. 2020 Apr 1;208:107477. https://doi.org/10.1016/j.pharmthera.2020.107477