They don’t call the gut “the second brain” for nothing. We’ve written about the critical gut-brain axis before, and it’s undeniable that the health and functioning of the small intestine have a major influence on mood and mental health. But it’s not only the gut that’s intimately tied to the brain. Happenings in the GI tract interact with the brain upstream of the intestines. Let’s take a closer look at the stomach-brain axis.

As is true for the gut-brain axis, there’s crosstalk between the stomach and brain—it’s a two-way communication system. The types of foods, the amount of food, and the way those foods are presented may all influence degree of satiation and satiety (desire to stop eating, as well as feeling full/satisfied for longer periods between meals), but even more interestingly, hormonal and nervous system communication from the stomach may also affect psychology and moods:

“…it is now well established that there are important links between the brain and the stomach that have significant effects on gastric function. However, the stomach also influences the brain. Disturbances in the crosstalk between the stomach and the brain may manifest as functional GI disorders while disturbances in the stomach-brain communication may also result in an altered regulation of satiety and as a consequence may affect eating behaviour and mood.” (Source)

Individuals who are trying to lose body fat may be advised to try to “fill up” on foods that provide bulk and volume for relatively few calories or carbohydrates so they might feel satiated without consuming excessive food energy. Foods that might fit this description include things like broccoli, cauliflower, zucchini, and other high-fiber, low-carb and low-calorie items. As one paper stated clearly, “Gastric distention during meal ingestion activates vagal afferents, which send signals from the stomach to the brain and result in the perception of fullness and satiety.”

It’s also recommended that people looking to lose body fat should drink water prior to meals, in order to fill up and ultimately end up eating less food. This advice is probably not the most effective, though, as many dieters can no doubt attest. You can’t fool biology: even if someone feels “full” after drinking a lot of water, crosstalk between the brain and stomach appears to be dependent on nutrient sensing, rather than simply stomach distension or the sensation of fullness.

A randomized, double-blind crossover study looking at this issue found that in healthy male volunteers, distension of the fundus or antrum (via intragastric balloon) resulted in reduced hunger and a concomitant feeling of fullness, but this purely mechanical distension did not trigger increased satiation. (After the distension period, subjects were free to eat and drink as much as they wished.)

Glucagon-like peptide-1 (GLP-1) is a hormone that inhibits food intake in animals and humans. A study looking at the effects of GLP-1 on satiety, hunger and food intake found that intravenous GLP-1 on its own induced a subsequent reduction in food and calorie intake, but the effects were even greater when GLP-1 was infused along with ingestion of a 400 mL protein shake. Compared to 400 mL water (also along with IV GLP-1), the protein shake “markedly increased” the inhibitory effect of GLP-1 on subsequent food intake. Subjects reported a decrease in hunger and an increase in satiety. The study was limited to a small number of healthy men, so the findings might not apply equally to everyone, but they’re still noteworthy.

The relationship between GLP-1 alone, and especially when combined with protein, may explain the efficacy of high-protein diets that are lower in carbs and calories for fat loss: protein is typically the most satiating macronutrient, and if people can consume relatively high amounts of protein and remain satisfied for sustained periods of time, they may be less likely to overconsume total calories, especially from carbs or fat. This might underlie the efficacy of protein-sparing modified fasts, which are used to induce rapid (but short-term) fat loss.

GLP-1 is secreted from L cells of the gastrointestinal mucosa in response to a meal, and is stimulated more by protein than by the other macronutrients. It slows gastric emptying and enhances pancreatic insulin secretion while suppressing glucagon secretion. For these reasons, GLP-1 receptor agonists (e.g., exenatide, liraglutide) are used as medications for lowering blood glucose. GLP-1 is degraded by the enzyme dipeptidyl-peptidase-IV (DPP-IV), so DPP-IV inhibitors (e.g., sitagliptin, vildagliptin) are also used as hypoglycemic medications.

GLP-1 appears to be a key player in protein-induced satiety, but one study concluded that the effects of protein pre-loading before subjects were free to eat and drink as much as they wished were not mediated by GLP-1 (nor by cholecystokinin or peptide YY, which also influence hunger and satiety). The oral protein pre-load reduced subsequent caloric intake by a substantial 19%, so whatever the precise mechanisms are, there’s no arguing that getting adequate protein is a key factor for healthy appetite regulation.

The satiety-inducing effects of protein may also relate to evolutionarily hard-wired sensing of nutrient status, particularly with regard to protein or amino acid sufficiency, a concept known as the Protein Leverage Hypothesis (PLH). In a nutshell, PLH posits that all animals—including humans—have an innate drive to get adequate protein, and when they don’t consume sufficient protein-rich foods, they will over-consume foods higher in fat and carbohydrate in a subconscious but biologically unavoidable effort to obtain their required protein. This drive for protein may be a factor in the obesity epidemic, as our dietary environment has become protein dilute compared to the evolutionary past, and we are awash in inexpensive refined carbohydrates and industrial fats.

Either way, the bottom line is that hunger and satiety are most definitely not all in our heads. Cravings and hunger that we may think are solely psychological in origin may stem from a complex interplay of signals from the stomach to the brain, and they’re very much physical rather than psychological. When people are genuinely hungry but are trying to lose body fat, filling up on water is neither effective nor a viable long-term strategy. Consuming protein, and making it the focal point of meals, with fibrous vegetables and healthy fats rounding things out, may better induce true satiety and satiation, and potentially reduce hunger and cravings that would otherwise drive people to snack between meals or overconsume energy at their next meal. Willpower rarely wins over biology.