The ketogenic “keto” diet and intermittent fasting have surged in popularity, embraced by everyone from weekend warriors to endurance athletes. These trends promise to harness the power of ketosis-a metabolic state where the body burns fat for energy instead of carbohydrates. Advocates tout its benefits, from weight loss to neuroprotection. One of the most appealing aspects of ketogenic diets is their potential to suppress appetite, making weight loss feel more manageable. But how does the keto diet achieve this, and what are the underlying mechanisms at play? This article delves into the science of appetite control on a keto diet, exploring the latest research and shedding light on the complex interplay of hormones, metabolic pathways, and brain function.
The Rise of Ketosis and Its Appetite-Suppressing Effects
Very-low-energy diets (VLEDs) and ketogenic low-carbohydrate diets (KLCDs) are two dietary strategies that have been associated with a suppression of appetite. Studies looking at patients prescribed a VLCD and hunger have shown that subjects who maintained beta-hydroxybutyrate levels of 0.3mM or greater had suppressed ghrelin levels, while those who were not in ketosis had ghrelin levels above baseline. To evaluate quantitatively the effect of ketogenic diets on subjective appetite ratings, we conducted a systematic literature search and meta-analysis of studies that assessed appetite with visual analogue scales before (in energy balance) and during (while in ketosis) adherence to VLED or KLCD. Individuals were less hungry and exhibited greater fullness/satiety while adhering to VLED, and individuals adhering to KLCD were less hungry and had a reduced desire to eat. Although these absolute changes in appetite were small, they occurred within the context of energy restriction, which is known to increase appetite in obese people. Thus, the clinical benefit of a ketogenic diet is in preventing an increase in appetite, despite weight loss, although individuals may indeed feel slightly less hungry (or more full or satisfied).
Ketogenic diets have become popular in recent decades for their demonstrated positive effects on weight loss, though the precise mechanism of action is not fully understood. The popularity of ketogenic diets in the treatment of obesity has increased dramatically over the last years, namely due to their potential appetite suppressant effect. Even though the exact mechanisms by which ketogenic diets suppress appetite remain to be fully determined, studies show that the more ketotic participants are (measured as β-hydroxybutyrate plasma concentration), the smaller is the increase in ghrelin and hunger and the larger is the increase in the release of satiety peptides.
Ketone Bodies: More Than Just Fuel
When deprived of glucose-its primary energy source-the body shifts gears, breaking down fat to produce ketones as an alternative fuel. Central to this process is beta-hydroxybutyrate (BHB), the most abundant ketone body. Usually the concentration of KB is very low (<0.3 mmol/L) compared to glucose (≅ 4 mmol). These alternative energy sources are the ketones bodies (KBs): acetoacetate (AcAc), β-hydroxybutyric acid (BHB) and acetone and the process of their formation occurring principally in the mitochondrial matrix in the liver is called ketogenesis.
Until now, scientists believed ketosis followed two main biochemical pathways: ketogenesis, which produces BHB in the liver, and ketolysis (or ketone oxidation) which consumes BHB for energy throughout the body. Long and his team weren’t so sure. They decided to take another look at what ketones, particularly BHB, were doing in the body. Rather than diving into the already contentious literature on the ketogenic diet’s downstream effects-such as its potential benefits for cognition or metabolic health-they decided to take a step back. In a series of experiments on mice and humans, the researchers manipulated the availability of BHB to explore how it influences metabolism and energy balance. What they found was a previously unknown metabolic "shunt pathway," where enzymes attach BHB to amino acids, producing a family of compounds they dubbed BHB-amino acids. The critical question remained: Are they inert byproducts, or do they actively influence the body’s response to ketosis?
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The researchers found that BHB-amino acids suppress feeding behaviors and promote weight loss, revealing a potent link between ketosis and energy regulation. The majority of the studies published over the last 2 years adds to previous evidence and shows that ketogenic diets suppress the increase in the secretion of the hunger hormone ghrelin and in feelings of hunger, otherwise see when weight loss is induced by non-ketogenic diets. Research done using exogenous ketones point out in the same direction.
Hormonal Harmony: Insulin, Leptin, and Ghrelin
Twenty-five years ago, the only known appetite-controlling hormone was insulin. When blood insulin levels are high, glucose gets stored as glycogen and fats get stored in adipose tissue. The resulting reduction in circulating fuels, such as glucose and free fatty acids, then stimulates appetite. In fact, many people are still arguing that increased insulin is the dominant signal that makes us become obese. But in the interim, we have discovered many other circulating and cellular signals that communicate the body’s energy status and regulate energy intake (aka appetite) as well as metabolism. Among these regulatory hormones are leptin (made primarily in adipose tissue), and ghrelin (made in the upper digestive tract). Both have specific receptors in the brain that transmit their biochemical message into behaviors - for leptin it is “eat less” and for ghrelin it is “eat more”.
Ghrelin, often referred to as the “hunger hormone”, is a multifaceted orexigenic hormone produced by the gut that, among other actions, influences acute meal initiation. Diet-induced weight loss is usually followed by a concomitant increase in ghrelin secretion and feelings of hunger, which may compromise weight loss goals and increase the risk of weight regain. The aim of this review is to describe the status of knowledge regarding the impact of ketosis, induced by diet or exogenous ketones (ketone esters), on appetite and the potential mechanisms involved. Ketogenic diets (KDs) have been shown to prevent an increase in ghrelin secretion, otherwise seen with weight loss, as well as to reduce hunger and/or prevent hunger. However, the exact threshold of ketosis needed to induce appetite suppression, as well as the exact mechanisms that mediate such an effect, has yet to be elucidated.
Leptin is satiety hormone that is secreted mainly by adipocytes and regulates energy intake as well as expenditure, in large part due to the leptin-responsive signaling cascades in the hypothalamus. What is interesting about leptin is that its influence extends beyond appetite regulation and it may have a complex role in the pathophysiology of obesity as well as immune function. Similar to what we see with insulin resistance, there is evidence of leptin resistance in individuals who are obese. This indicates that while obesity often coincides with increased circulating leptin levels, there is a resistance to its anorexigenic signals to reduce food intake.
The Brain-Gut Connection: A Complex Network
Hunger and satiety are two important mechanisms involved in body weight regulation. Even though humans can regulate food intake by will, there are systems within the central nervous system (CNS) that regulate food intake and energy expenditure. This complex network, whose control center is spread over different brain areas, receives information from adipose tissue, the gastrointestinal tract (GIT), and from blood and peripheral sensory receptors. The actions of the brain's hunger/satiety centers are influenced by nutrients, hormones and other signaling molecules. The hypothalamus is the brain's main center responsible for hunger/satiety (H/S) control. The gastrointestinal tract (GIT) plays a central role in the control of energy balance. Many molecules produced by the GIT exert hunger or satiety effects on the brain.
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These are sites of convergence and integration of many central and peripheral signals, not just macronutrients, that are involved in food intake and energy expenditure mechanisms, e.g., a group of neurons in the ARC stimulating food intake via neuropeptide Y (NPY) and agouti gene-related protein (AGRP). These neurons interact with those producing the anorexigenic pro-opiomelanocortin (POMC) and the cocaine/amphetamine-regulated transcript (CART) (Williams et al., 2001). The SS providing information to the brain mainly send information to the nucleus of the solitary tract (NTS). These signals are generated in the GIT and abdominal viscera, as well as in the oral cavity and provide information about mechanical and chemical properties of food. The ASs arrive to the median eminence through ARC or through the blood-brain barrier (BBB). Hormones like leptin and insulin, both secreted into the blood, reflect the stored body fat. These hormones can pass the BBB and stimulate specific receptors.
Inflammation and Appetite: A Vicious Cycle
This paradox of increased appetite and obesity occurring despite elevated blood leptin levels may be partially attributable to inflammation. You may have heard obesity referred to as a chronic low-grade inflammatory state, but in this instance, leptin resistance may be due to enhanced immune and inflammatory responses in the brain. The neuroregulatory aspects of appetite have made it clear that the brain and central nervous system (CNS) are involved in energy homeostasis and food-seeking behaviors. Thus, as the master regulator of appetite, the hypothalamus integrates peripheral and central pathways to mediate appetite signals.
In fact, an up-regulation of pro-inflammatory pathways in the hypothalamus, triggered by a pro-inflammatory diet rich in a combination of sugar and saturated fat, has been shown to effect chronic energy imbalance and changes in fat mass. Because leptin acts within the hypothalamus, the over-activation of immune cells associated with the hypothalamus can impair leptin signaling. This multi-dimensional inflammatory response likely begins before overt obesity and contributes to the overall development of metabolic dysfunction. Since we now know that inflammation is dramatically reduced by sustained nutritional ketosis, it appears that the reduction in leptin resistance due to reduced inflammation more than compensates for the lower leptin levels.
Practical Implications and Future Directions
Future studies should investigate the minimum level of ketosis required to achieve appetite suppression during ketogenic weight loss diets, as this could enable inclusion of a greater variety of healthy carbohydrate-containing foods into the diet. The challenge of losing weight and then keeping it off can be daunting, especially if you have ridden the diet roller-coaster in the past. Dieting, exercise and repeated feats of sheer willpower are typically met with temporary weight loss followed by weight regain and mounting frustration. If you feel like whenever you count and/or restrict calories your appetite begins a progressive climb the longer you purposefully count or restrict your calorie intake, you may be on to something. Our bodies have an innate survival mode that kicks in to maintain energy balance when our stored energy reserves (i.e., body fat) are threatened. Obesity and metabolic diseases, like type 2 diabetes, can perturb these natural signals the body uses to regulate appetite and energy balance, making weight loss even more difficult.
For many of our readers, this is probably more than enough science. For the rest of you, what follows are the details and additional references that back up this very complex but important story. Now We Know Why You Can Lose Weight with Reduced Hunger and Cravings. Preliminary scientific reports seem to support this phenomenon, and the evidence shows that KD is more effective, at least in the short/medium-term, on fat loss. A recent study by our group has demonstrated that a brief ketogenic period, if followed by a longer period of correct Mediterranean diet could avoid this yo-yo effect. During the ketogenic period subjects reported less hunger, confirming previous studies on hunger-suppression effect of ketogenic diet.
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