on August 21, 2026
Our eating behavior is not governed by a simple calorie count. The brain continuously integrates information from the digestive system, adipose tissue, pancreas, muscles, and the body's energy availability. It is an evolutionary system aimed primarily at survival: maintaining body temperature, acquiring energy, avoiding nutritional deficiency, and preserving reproductive capacity.
For this reason, a calorie does not necessarily represent the same biological signal in every situation. The body perceives not only the energy contained in a food, but also its volume, texture, rate of absorption, presence of fiber, protein, and fat, the state of energy reserves, and the time of intake.
One of the first key players in this system is the stomach. Ghrelin, produced mainly by the gastric mucosa, increases before a meal and decreases after food intake. At the hypothalamic level, it stimulates neurons that produce NPY and AgRP, two important orexigenic mediators, i.e., capable of promoting food intake.
This helps explain a fundamental difference between a highly energetic but unstructured food and a bulky, high-fiber food. A sugary drink, a dessert, or a refined food may provide energy without producing the same degree of gastric distension and mechanical stimulation of the digestive system as a meal consisting, for example, of vegetables, legumes, whole grains, and seeds.
In fact, dietary fiber acts through several mechanisms simultaneously: it increases the volume of gastric contents, can slow down gastric emptying, alters nutrient availability, and, when fermented by the gut microbiota, generates short-chain fatty acids capable of influencing enteroendocrine cells. These cells produce hormones involved in appetite regulation, including GLP-1 and PYY.
The result is not simply "eating less". It is the ability to generate a satiety signal more consistent with the quantity and structure of the meal.
The gut-brain system: CCK, GLP-1, and PYY
Satiety is the result of a network of signals. Among the most studied are cholecystokinin (CCK), GLP-1, and peptide YY (PYY).
CCK is released mainly in response to the presence of nutrients in the intestine, particularly fats and proteins, and participates in reducing food intake and slowing gastric emptying. GLP-1, produced by L enteroendocrine cells, instead contributes to the regulation of satiety, slows gastric emptying, and enhances glucose-dependent insulin secretion.
PYY is produced mainly in the ileum and colon and increases after a meal, contributing to the regulation of appetite and gastrointestinal motility.
However, it is important not to turn these mechanisms into an oversimplification: increasing a single incretin does not automatically equate to losing weight. The physiological response to food is complex, and the effects of individual meals on CCK, GLP-1, and PYY levels do not always translate into a significant reduction in energy intake over the long term. In fact, a review of 70 human studies highlighted precisely the difference between the pharmacological effects of these peptides and those obtained simply through diet.
The general direction, however, is clear: whole foods, rich in fiber and with an adequate content of protein and fat, tend to produce a more complex satiety response compared to highly refined and rapidly absorbable products.
It is not just a matter of calories
Saying that food quality matters does not mean stating that calories are irrelevant. Energy balance remains fundamental to changes in body weight.
The difference lies in the fact that the body does not treat all calories the same way. A meal rich in fiber and protein can lead to greater satiety, slower digestion, and a different glycemic response compared to an energetically equivalent amount of sugars and refined flours.
This is particularly important when considering the relationship between diet and insulin.
Insulin is produced by pancreatic beta cells mainly in response to an increase in blood glucose, but also to other nutritional signals. It facilitates the use and storage of nutrients, promoting glycogen synthesis and, when available energy exceeds the body's needs, also storage in the form of fat.
It is therefore not correct to consider insulin as a "bad hormone". On the contrary, it is essential for life. The problem arises when the body is chronically subjected to high energy availability, physical inactivity, alterations in insulin sensitivity, and poor-quality diet.
In this context, a diet frequently based on readily available sugars and refined products can promote wide fluctuations in blood glucose and insulin levels, especially when these foods are consumed in large quantities and in the absence of fiber, protein, and other components capable of slowing absorption.
However, the concept of "insulin spike = weight gain" is too simplistic. Insulin is also necessary for normal muscle glycogen replenishment after exercise and for numerous anabolic processes. It is the overall metabolic context that determines whether the system functions in a physiological or pathological way.
Inflammation, resistin, and metabolism
Another important link concerns adipose tissue and inflammation.
Resistin is a molecule belonging to the adipocytokine/cytokine family and has been studied for its possible involvement in insulin resistance and inflammation. However, an important clarification is necessary: in humans, resistin does not behave exactly as it does in mouse models.
In mice, it is produced mainly by adipocytes; in humans, the main source is immune cells, particularly monocytes/macrophages. For this reason, it is not scientifically correct to simply state that "high resistin causes weight gain". The literature suggests instead an association between resistin, inflammation, obesity, and metabolic alterations, with a causal relationship in humans that is still not fully defined.
A meta-analysis of human studies found a positive, but relatively weak, correlation between resistin and insulin resistance in people with obesity or type 2 diabetes.
This is an important example of how physiology must be interpreted by avoiding overly simple causal relationships: inflammation, adipose tissue, insulin resistance, and appetite alterations form an interconnected network, not a single linear chain.
Adiponectin: a metabolically favorable signal
Adiponectin is also produced in adipose tissue, a protein with important metabolic effects. Unlike many other adipocytokines, adiponectin levels generally tend to be lower in obesity and are associated with better insulin sensitivity.
Adiponectin promotes fatty acid oxidation and contributes to the regulation of glucose and lipid metabolism. However, its relationship with weight loss is more complex than a simple cascade reaction in which "less fat determines more adiponectin and therefore even more weight loss".
The reduction of adipose mass can favorably alter the adipocytokine profile, but weight loss remains the result of the interaction between energy balance, diet, physical activity, endocrine regulation, sleep, and behavioral factors.
Muscle as an endocrine organ: the case of irisin
Skeletal muscle is not merely a tissue dedicated to movement. During physical activity, it produces numerous myokines, signaling molecules that can influence other tissues.
Among these, irisin, derived from the FNDC5 precursor, has been studied. Experimental research has suggested its involvement in the "browning" of adipose tissue and thermogenesis. However, the translation of these mechanisms into a clinically relevant weight-loss effect in humans is still under study.
The most recent evidence is interesting: a 2026 meta-analysis of 50 studies involving 1,780 overweight or obese participants found an increase in circulating irisin after exercise programs, along with other favorable metabolic adaptations.
Other meta-analyses have also found increases in irisin after exercise, but with significant heterogeneity among the studies and methodological issues in measuring the molecule.
For this reason, it is more accurate to say that physical activity activates a network of muscle-adipose-metabolic signals in which irisin represents one of the possible mediators, rather than attributing the responsibility for weight loss to this single molecule.
The practical principle remains extremely solid: regular movement, combining aerobic activity and strength training and appropriately modulating intensity, improves the body's ability to use energy substrates and preserves muscle mass during weight loss.
The timing of when we eat matters
Even when we eat seems to have a metabolic significance.
Metabolism is regulated by the circadian clock, and numerous endocrine processes show fluctuations over the 24-hour period. Observational and experimental studies suggest that concentrating energy intake in the early hours of the day and reducing late eating may favor certain metabolic parameters compared to predominantly evening eating.
This does not mean, however, that a calorie consumed at 8:00 a.m. is automatically "burned" and a calorie consumed at 10:00 p.m. is automatically converted into fat. The relationship is much more complex.
A systematic review on the role of chronotype found a consistent association between evening preference, less favorable eating habits, and a higher prevalence of obesity, while a more recent review on chrononutrition highlights potentially independent effects of meal timing on metabolism, while emphasizing the need for longer and more controlled studies.
The most useful message is therefore to align, as much as possible, eating, activity, and sleep with the circadian rhythm, especially avoiding the combination of very large meals, sedentary behavior, and nighttime eating.
Proteins: the building blocks of metabolism
A metabolically efficient organism also needs an adequate protein intake.
Proteins are not only used to build muscles. They are essential for enzymes, receptors, transporters, antibodies, cytokines, plasma proteins, and numerous hormones and biological mediators.
For healthy adults, the EFSA indicates a Population Reference Intake of 0.83 g of protein/kg of body weight per day. The requirement may increase in specific physiological or pathological conditions, including growth, pregnancy, breastfeeding, and certain situations associated with physical activity or muscle mass loss.
This does not mean that it is necessary to systematically resort to extremely high intakes. Rather, it means that, especially during calorie restriction, the adequacy of protein intake becomes important for preserving lean mass.
Plant proteins can contribute significantly to meeting the requirement through legumes, whole grains, nuts, and seeds. The combination of different plant sources throughout the day also allows for an overall adequate amino acid profile.
Fiber as a central element
Among all the components of the diet, dietary fiber occupies a special position because it acts simultaneously on the gastrointestinal tract, metabolism, and microbiota.
A diet rich in whole plant foods increases meal volume, slows down the rate of carbohydrate absorption in many cases, and provides substrates for intestinal bacterial fermentation.
Short-chain fatty acids produced by fermentation, particularly acetate, propionate, and butyrate, can interact with receptors present on enteroendocrine cells and promote the production of signals such as GLP-1 and PYY.
A recent scoping review from 2026, which analyzed 52 studies involving over 1,000 participants, confirms that some fibers can increase GLP-1 and/or satiety, but also highlights the strong heterogeneity of the results and the prevalence of short studies.
Fiber should therefore not be considered simply as a remedy for constipation. It is an integral part of the communication between food, the intestine, the microbiota, and the brain.
For this reason, in dietary practice, it is generally preferable to favor vegetables, whole fruit, legumes, whole grains, nuts, and seeds over products obtained from refining and subsequent industrial reconstruction of the food.
However, a clarification is also needed here: there are no real "negative calories". Celery or other very low-energy vegetables can have a significant digestive and thermal cost compared to the energy they provide, but it is not correct to say that eating them causes you to consume more energy than you take in. Their advantage lies rather in their high nutrient density and low energy density.
The same principle applies to fruit. Whole fruit contains water, fiber, and micronutrients and generally has a relatively low energy density. This does not mean that it is metabolically equivalent to a sugar-free food or that its consumption can be considered unlimited regardless of the overall energy balance.
The fundamental point is another: the structure of the food matters. A whole apple is not physiologically equivalent, given the same theoretical amount of sugar, to a sweetened beverage. Chewing, volume, fiber, and ingestion speed change the body's response.
The biological principle that emerges
Body weight regulation is therefore the result of an extremely sophisticated system in which mechanical, hormonal, metabolic, and nervous signals converge.
Ghrelin communicates the state of hunger and participates in the activation of NPY/AgRP neurons; gastric distension and intestinal signals contribute to satiety; CCK, GLP-1, and PYY modulate eating behavior; insulin and leptin inform the brain about energy availability and reserves; adiponectin and other adipokines participate in the regulation of metabolism; muscle, through myokines, communicates with the rest of the body; the circadian clock finally establishes part of the temporal context in which all this happens.
It is precisely this complexity that makes the idea that simply "eating less" would be sufficient to lose weight reductive. An energy deficit remains essential for losing body mass, but the quality of the diet largely determines how easily that goal can be achieved and maintained, influencing hunger, satiety, diet adherence, muscle mass, glycemic response, intestinal health, and eating behavior.
The strategy most consistent with physiology is therefore to build the diet around minimally processed foods, adequate fiber, sufficient protein intake, good-quality fats, an abundance of plant-based foods, reduced free sugars and ultra-processed foods, regular meals, adequate sleep, and physical activity.
It is not a matter of fighting metabolism, but of stopping to continuously send it contradictory signals.
Bibliographic references
- Cummings DE, Overduin J. Gastrointestinal regulation of food intake. J Clin Invest. 2007;117(1):13-23.
- Müller TD, Nogueiras R, Andermann ML, et al. Ghrelin. Mol Metab. 2015;4(6):437-460.
- Murphy KG, Bloom SR. Gut hormones and the regulation of energy homeostasis. Nature. 2006;444:854-859.
- Slavin JL, Green H. Dietary fibre and satiety: the effects of fiber on appetite. Nutr Bull. 2007;32(s1):16-23.
- Alamshahi A, et al. The role of dietary fibers in regulating appetite, an overview of mechanisms and weight consequences. Crit Rev Food Sci Nutr. 2022.
- Drucker DJ. Mechanisms of Action and Therapeutic Application of Glucagon-like Peptide-1. Cell Metab. 2018;27(4):740-756.
- Batterham RL, Cowley MA, Small CJ, et al. Gut hormone PYY(3-36) physiologically inhibits food intake. Nature. 2002;418:650-654.
- Batterham RL, et al. Studies on dietary fibre, gastrointestinal hormones and appetite regulation.
- Teixeira GP, et al. Role of chronotype in dietary intake, meal timing, and obesity: a systematic review. Nutr Rev. 2022;81(1):75-90.
- Chaix A, Manoogian ENC, Melkani GC, Panda S. Time-restricted eating to prevent and manage chronic metabolic diseases. Annu Rev Nutr. 2019;39:291-315.
- EFSA NDA Panel. Scientific Opinion on Dietary Reference Values for protein. EFSA Journal. 2012;10(2):2557. EFSA sets a PRI of 0.83 g/kg/day for adults.
- Steppan CM, Bailey ST, Bhat S, et al. The hormone resistin links obesity to diabetes. Nature. 2001;409:307-312.
- Silswal N, Singh AK, Aruna B, et al. Human resistin stimulates the proinflammatory cytokines TNF-α and IL-12 in macrophages. Biochem Biophys Res Commun. 2005;334:1092-1101.
- Lee JH, et al. Relation of circulating resistin to insulin resistance in type 2 diabetes and obesity: a systematic review and meta-analysis.
- Boström P, Wu J, Jedrychowski MP, et al. A PGC1-α-dependent myokine that drives brown-fat-like development of white fat and thermogenesis. Nature. 2012;481:463-468.
- Qiu S, et al. The effect of exercise interventions on irisin level: a systematic review and meta-analysis of randomized controlled trials. EXCLI J. 2022;21:1235-1250.
- Hejazi K, et al. Effects of Different Training Modalities on Circulating Irisin Levels in Overweight and Obesity Adults: A Systematic Review and Meta-analysis of Randomized Controlled Trials. Sports Med. 2026.
