The rise of GLP-1 receptor agonists such as Ozempic, Wegovy, Zepbound, and Mounjaro now accounts for a global pharmaceutical market share in the tens of billions of dollars annually – estimated in 2024 to be $53 billion and expected to grow to $150 billion by 2030.

These wonder drugs developed originally as a therapeutic tool for diabetes (and coupled with a healthful diet they’re a good one for that) are famously now being employed for weight loss in the broader non-diabetic (and sometimes not even particularly overweight) population, but also for a crazy quilt array of other conditions, including: cardiovascular risk reduction (for which they’ve gained FDA approval), obstructive sleep apnea tied to obesity, slowing the progression of chronic kidney disease, improving fatty liver disease, protecting against Alzheimer’s and other dementias, and such off label applications as reducing the craving for alcohol and other addictive substances, lowering blood pressure, improving lipid profiles, increasing insulin sensitivity in PCOS, and possible roles in alleviating chronic pain, strengthening bones in osteoporosis, and reducing seizures. And who knows what else in the offing?

What is the underlying mechanism that could account for their purported effect in so many disparate body systems? The GLP-1 receptor. The specific receptor that these GLP-1RA drugs agonize exists in all these disparate tissues, and stimulating it results in these various actions across different tissues.

How GLP-1 Receptors Work

For example, in the liver, the activation of the GLP-1 receptor reduces fat accumulation through inhibiting fatty acid synthesis and enhancing insulin signaling to boost glucose uptake and tamp down glucose production, with the end result of lowering blood glucose and ridding the liver of fat. GLP-1 receptor activation also decreases inflammation and fibrosis in the liver through suppressing the release of inflammatory cytokines and dampening inflammasome activation.

In the brain, GLP-1 signaling in the hypothalamus, hippocampus, and brain stem mediates neuroprotective mechanisms that reduce neuroinflammation, enhance brain cell survival, suppress the accumulation of amyloid/tau protein, and modulate appetite.

In the bones, GLP-1 promotes the activity of osteoblasts (the cells that build new bone) and suppresses the activity of osteoclasts (the resorptive cells responsible for cleaning out old or damaged bone). The result of that balance shift would be bone building.

In adipose tissue, GLP-1 activity promotes the breakdown of fat and the activation of brown adipose tissue (via central nervous system signaling – more about which in a moment) to enhance energy expenditure. This activation of GLP-1 receptors reduces inflammation in the adipose tissue, lowers production of inflammatory cytokines, reduces stress on the endoplasmic reticulum (the structure responsible for assembling and transporting proteins produced in the cell), and restores normal adipose metabolism, which improves insulin sensitivity.

An amazing diversity of beneficial actions to be sure.. But they come with the potential for a laundry list of unfavorable actions that are at present being documented apace, with a new report of untoward possible side effects of these drugs seeming to come out almost weekly.

• Gastrointestinal symptoms include nausea, vomiting, diarrhea or constipation (the most common side effects), gastroparesis (stomach sluggishness), abdominal pain, bloating, stomach upset, heartburn, early satiety, and appetite loss.
• Systemic symptoms and other common effects include injection-site reactions (redness, pain, nodules), headache, fatigue, dizziness, too-rapid weight loss resulting in skin laxity and changes especially in the face, hair loss, decreased libido, suicidal thoughts, and most recently chronic cough has been added as a possible untoward side effect.

But shooting up with a GLP-1RA medication (or taking the pills now in development) isn’t the only way to raise your GLP-1 and garner all its many potential health benefits. And you can do it without the potential risk of bad effects.

The Role of Food

GLP-1 receptors are scattered throughout the body for a reason—and the reason isn’t to respond to a GLP-1 receptor agonist. They’ve been sitting there in our guts and throughout the body for many millennia to respond to the incretin GLP-1 (glucagon-like peptide-1) produced by the L-cells in our intestines. GLP-1 is one of a pair of incretins (the other being GIP—glucose-dependent insulinotropic peptide) that developed in our evolution as modern humans to sense and respond appropriately to incoming dietary fuels and nutrients. GIP is produced by what are called K-cells in the proximal (closest to the stomach) part of the gut and GLP-1 in the L-cells in the distal (farther away from the stomach) part of the intestine. They seem to have arisen when the glucagon-producing and insulin-producing cells now within the pancreas migrated out of their original location in the intestinal lumen (where they risked being damaged by incoming toxic insults) to a still-connected but more protected location. These L and K cells sense incoming protein, fat, and carbohydrate and elaborate their products (GLP-1 and GIP) to amplify the information about what food is coming down the pipe, then relay that message to their receptors in other parts of the body to stimulate various actions needed to make best use of the incoming nutrients and fuels.

Dietary carbohydrate is the strongest stimulus for the release of GIP, which amplifies the call for insulin to handle the incoming glucose load. In the absence of much incoming carbohydrate, as would be the case on a low-carb ketogenic diet, incoming fat and protein will also stimulate its release. However, the lack of substrate (i.e., little incoming glucose) blunts the insulin response GIP would otherwise engender. Fat and protein stimulation of GIP amplifies the release of insulin’s counter-regulatory hormone, glucagon, which serves to keep blood sugar from dropping too low. And GIP exerts broad metabolic effects beyond amplifying the glucose signal that impact nutrient partitioning and preserve beta-cell function. It’s a powerful incretin in its own right, but, this discussion will focus on GLP-1.

So what naturally causes the L-cells to produce GLP-1? Just as with GIP, it’s food. And the foods that do it best will probably come as no major surprise to anyone who’s been in the BSI/MetFix universe for any length of time.

• Protein-rich foods are the most potent stimulators of GLP-1 release from the gut. Lean meats, poultry, fish and seafood, eggs and egg whites, yogurt and other dairy, soy, and other legumes all increase postprandial GLP‑1 and promote satiety. Their release is acute and robust, but not long lasting. The effect can be prolonged by lower gut bacterial action on fermentable fibers (see below) to produce short-chain fatty acids (propionate, butyrate, etc.)
• Healthful naturally-occurring animal fats such as tallow, lard, butter, and schmalz, the oils of fatty fish (salmon, mackerel, sardines, trout) and fruit and nut oils (coconut oil, olive oil, avocado oil, macadamia nut oil) activate free fatty acid receptors on L‑cells to stimulate the release of GLP-1 from the gut and prolong its activity.There was early research that seemed to indict a diet high in saturated fats (what a surprise) as potentially toxic to the L-cells over time, but all that research was done in isolated cell models or high-fat/high carb rodent diets, not in a ketogenic diet context in humans. Subsequent work done in low-carb/high-sat-fat diets appears to find no evidence of L-cell loss and some data even showed enhancement of GLP-1 responses long term.
• High‑fiber and fermentable‑fiber foods play a role in prolonging GLP-1 activity once gut bacteria ferment them into short-chain fatty acids that can then stimulate the GLP-1 receptors in the lower gut. But because that process takes a bit of time, the effect isn’t immediate. Such foods as whole grains, legumes (beans, lentils, chickpeas, field peas), fibrous vegetables (Brussels sprouts, broccoli, carrots, artichokes, asparagus, cabbage, onions, garlic) and fruits (apples, pears, citrus, tomatoes, green bananas, and avocado) aren’t potent stimulators of immediate GLP-1 release but do prolong the effect.

Not much naturally gut-derived GLP-1 makes it through to the brain because it is ephemeral (a lifespan of only a couple of minutes) and too large to pass the blood-brain barrier (BBB). The GLP-1RAs are also too large to cross the BBB, but they are engineered for longevity of drug effect so that it lasts in the blood for 12+ hours. As such, unlike native GLP-1 the drug can hang around long enough to exert some secondary central effects that may affect the brain, protecting it by reducing inflammation, and also curbing appetite. Is that an advantage?

GLP-1 and the Brain

Not especially. And here’s why. The brain effects brought about by GLP-1 activity are not the result of GLP-1 or GLP-1RA circulating in the blood. They are the result of GLP-1 produced locally within the brain by the neurons themselves. And what stimulates the neurons to produce GLP-1? One trigger is the release of the neuropeptide hormone CCK (cholecystokinin) which occurs when a meal of fat and protein enters the first portion of the gut. Another is gastric (stomach) distention, which naturally occurs when you eat a filling, whole food meal. So the effect of what you eat impacts the brain as well.

The extraordinary therapeutic promise of GLP‑1 receptor agonists underscores a powerful irony: the very mechanisms that make these drugs so effective across multiple organ systems are already built into the human body, waiting to be activated by the right food, not just a needle. While GLP‑1RAs offer impressive benefits—from weight loss and metabolic improvement to potential neuroprotection and cardiovascular and renal protection—their growing list of adverse effects reminds us that mimicking physiology with pharmacology is not risk‑free.

A diet built around whole proteins, healthy fats, and fiber-rich vegetables isn’t just “eating well” in some vague, aspirational sense; it is a precise, evidence-based strategy for engaging one of the body’s most powerful and wide-ranging signaling systems. By harnessing it, individuals can naturally stimulate their own GLP‑1 and GIP systems, support metabolic health, and reap many of the same benefits without the uncertainties of long‑term drug use. In this light, the best GLP‑1 strategy may not be in the pharmacy, but on the plate.

If you have patients and clients who wonder whether taking the shots might be the right move, first tell them there’s a way they can naturally raise their GLP-1 (and GIP). Eat satisfying, whole food meals of meat, fish, poultry, eggs, dairy, nuts and seeds, leafy greens, fresh vegetables, a few fruits, little starch, and no sugar. All the pleasure and none of the risk.