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Ketosis-Mediated Appetite Control: Disrupting the Ghrelin-Driven Hunger Cycle Through Metabolic Reprogramming in Obesity Management and Weight Maintenance Prevention

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dr. Karunia Valeriani Japar

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Introduction

Weight loss maintenance remains a formidable challenge in the management of obesity, with many individuals experiencing substantial weight regain following successful diet-induced fat loss. This relapse is frequently attributed to physiological adaptations that promote increased appetite, cravings, and changes in hormonal signalling, such as upregulated ghrelin and suppressed satiety hormones, which together enhance the drive to eat and reduce the like hood of sustained weight loss. Adaptative decreases in resting energy expenditure further exacerbate this vulnerability, establishing a powerful “hunger cycle” that undermines long-term success [1,2,3,4].

Recent research has turned to the ketogenic diet (KD), a very low carbohydrate, high fat nutritional approach that induces a metabolic state of ketosis, as a potential intervention to. Modulate these compensatory responses. While the ketogenic diet is well-established for short term weight loss, emerging data suggest that nutritional ketosis may offer unique advantages for appetite regulation and weight maintenance beyond the calorie deficit alone. Mechanisms may include direct effects of ketone bodies on hunger mediating hormones and neural pathways, as well as improved glycemic control and metabolic flexibility [1,2,5].

This review synthesizes the current scientific understanding of how ketosis may influence post-diet appetite and weight stability, integrating the pivotal findings from the 2013 European Journal of Clinical Nutrition study and subsequent literature. By elucidating the relationship. Between ketosis, appetite regulation, and long-term fat loss, this article aims to inform innovative obesity management strategies and support the prevention of metabolic disease relapse [3,4].

Challenges in Weight Loss Maintenance: Physiological Adaptation

Weight loss maintenance represents one of the most formidable challenges in obesity management, with epidemiological data indicating that 80 to 95 percent of individuals who successfully lose weight regain some or all of it within one to five years. While behavioural factors such as dietary adherence and physical activity play important roles, accumulating evidence demonstrates that weight regain is predominantly driven by powerful physiological adaptations that actively promote the restoration of lost body mass. These compensatory mechanisms, encompassing alterations in appetite regulating hormones, reductions in energy expenditure, and changes in. metabolic efficiency, create a biological environment that favours energy intake over expenditure, establishing what has been termed the “hunger cycle” [6,7,8].

Why Weight Regain Is Common After Dieting

The human body regulates body weight and adipose tissue mass through complex neuroendocrine systems that have evolved to defend against weight loss and maintain energy stores. When individual achieve weight loss through caloric restriction, the body interprets this state as a potential threat to survival and activates multiple compensatory pathways designed to restore energy balance. These adaptations are not transient responses but rather persistent physiological changes that can endure for at least one year following initial weight reduction, and in some cases, extend for several years [6,7,9].

Figure 1. Factors Affecting Energy Balance and Thus Steady-State Weight [6]

Research demonstrates that the magnitude of weight loss strongly predicts subsequent weight regain, with smaller initial weight losses paradoxically associated with higher rates of relapse. This phenomenon reflects the body’s homeostatic regulation, where the hypothalamus integrates signals regarding food intake, energy balance, and body weight to coordinate appropriate counter-regulatory responses. The persistence of these adaptations helps explain why weight loss maintenance requires sustained vigilance and deliberate effort to resist heightened hungers signals, rather than simply representing a failure of willpower [6,10].

Overview Of Adaptive Changes: Increased Appetite, Altered Hormonal Signalling (E.G., Ghrelin, Leptin, Glp-1)

One of the most significant physiological adaptations following weight loss involves profound alterations in circulating appetite regulating hormones. These hormonal changes uniformly favour increased hunger, reduced satiety, and enhanced energy storage, creating a powerful biological drive toward weight regain [6,11].

Ghrelin is an orexigenic (appetite-stimulating) hormone produced primarily in the stomach that signals hunger by acting on hypothalamic feeding centres. Following diet-induced weight loss, total ghrelin concentrations increase significantly, with meta-analyses demonstrating consistent elevations across interventions involving caloric restriction, exercise or combined approaches. The magnitude of ghrelin elevation correlates directly with the extend of weight loss achieved. Importantly, these elevated ghrelin levels persist for at least one year after initial weight reduction, contributing to sustained increases in subjective appetite and food-seeking behaviour. Studies have shown that individuals with greater decreases in ghrelin during weight loss exhibit higher odds ratios for subsequent weight regain, while those who maintain more stable ghrelin levels demonstrate better long-term weight maintenance [9,11,12,13].

Leptin, the “satiety hormone” produced by adipose tissue, functions to inhibit hunger and promote feelings of fullness by signalling the brain about the body’s energy stores. Weight loss results in substantial reductions in circulating leptin levels proportional to the decrease in fat mass. These leptin reductions persist for at least one year following weight loss and contribute to increased hunger and decreased energy expenditure through effects on the hypothalamus. Research indicates that higher baseline leptin levels and smaller reductions in leptin during weight loss predict greater subsequent weight regain. The decreased leptin signalling following weight loss creates a state of perceived energy deficiency that the brain interprets as starvation, triggering compensatory mechanisms to restore body weight [6,10,12,13].

Peptide YY (PYY), a satiety hormone secreted from intestinal L-cells in response to food intake, suppresses appetite and promotes feelings of fullness. Weight loss leads to significant reductions in both fasting and post prandial PYY concentrations, with these changes persisting for at least one year after initial weight reduction. Meta-analyses have documented decreases in total PYY following dietary-induced weight loss, contributing to reduced satiety signals and increased food intake. Importantly, postprandial PYY secretion remains significantly lower in weight reduced individuals compared to never-obese controls matched for body composition, suggesting that the reduction represents a compensatory adaptation rather than simple normalization [9,14,15].

Glucagon-like peptide-1 (GLP-1) is an incretin hormone that promotes satiety through multiple mechanisms, including stimulation of glucose-dependent insulin release, slowing of gastric emptying suppression of glucagon secretion, and direct effects on hypothalamic appetite centres. Following weight loss, both fasting and postprandial active GLP-1 concentrations decline significantly. These reductions persist throughout the weight maintenance phase and contribute to decreased feelings of fullness after meals. Studies comparing weight reduced individuals to weight-stable controls demonstrate that postprandial GLP-1 responses remain significantly blunted even one year after achieving weight loss, independent of current body composition [6,15,16,17,18,19].

Cholecystokinin (CCK) another important satiety peptide released from the small intestine in response to fat and protein intake, also shows persistent reductions following weight loss. Postprandial CCK concentrations remain significantly lower in weight reduced individuals compared to never obese controls for at least one year, contributing to reduced satiety signalling and increased vulnerability to overeating [6,15].

Collectively, these hormonal adaptations, increased ghrelin combined with decreased leptin, PYY, GLP-1 and CCK, create a perfect storm for weight regain by simultaneously enhancing hunger signals while diminishing satiety responses. A landmark study published in the New England Journal of Medicine in 2011 demonstrated that one year after initial weight reduction. The circulating levels of appetite mediating hormones that encourage weight regain do not revert to pre-weight loss values, with corresponding persistent increases in subjective hunger ratings. These findings fundamentally challenged the assumption that hormonal adaptations would normalize over time and highlighted the need for long-term strategies to counteract these persistent changes [6,9].

The Role Of Energy Expenditure And Metabolic Adaptation In Post Diet Relapse

In additional to hormonal changes favouring increased appetite, weight loss triggers substantial reduction in energy expenditure that further promote weight regain. These decreases occur across all components of total daily energy expenditure (TDEE), including resting energy expenditure (REE), non-resting energy expenditure (NREE), and the thermic effect of food [6,20].

Adaptive thermogenesis (also termed metabolic adaptation) refers to a reduction in energy expenditure that exceeds what would be predicted based solely on changes in body composition, such as losses of fat mass and fat-free mass. This phenomenon represents a biological survival mechanism that conserves energy in response to perceived starvation. Resting metabolic rate, which accounts for approximately 60-70% of TDEE in most individuals, consistently shows disproportionate decreases following weight loss [21,22,23,24].

The magnitude of metabolic adaptation can be substantial. Studies have documented reductions in REE ranging from 100 to 500 kcal per day beyond what would be expected from changes in body mass and composition. In the widely publicized “Biggest Loser” study, participants experienced an average metabolic adaptation of approximately 500 kcal per day at the end of the 30-week competition, with this adaptation persisting at six years despite substantial weight regain. Importantly, those maintaining greater weight loss at six years also demonstrated greater concurrent metabolic slowing, suggesting that adaptive thermogenesis represents a proportional response to efforts to maintain reduced body weight [6,23,25].

The persistence of metabolic adaptation during weight maintenance remains somewhat controversial, with studies showing variable results depending on the intervention type, duration of weight loss, and measurement methods. Some research indicates that adaptive thermogenesis develops during active weight loss and persists throughout a 44-week weight maintenance period. Other studies suggest that metabolic adaptation may partially recover after weight stabilization, particularly following bariatric surgery. However, a comprehensive analysis of caloric restriction trials demonstrated that RMR reductions persist during prolonged weight maintenance, with approximately 60% attributed to loss of energy-expending tissues (primarily skeletal muscle and adipose tissue) and 40% attributed to true metabolic adaptation—defined as reduced metabolic activity of remaining tissues [20,21,23,27].

Non-resting energy expenditure also decreases significantly following weight loss, accounting for a substantial proportion of the total energy expenditure decline. Studies have documented that NREE reductions can account for approximately 70% of the decrease in 24-hour energy expenditure following weight loss. This decrease occurs partly due to reduced body mass requiring less energy for physical activity, but also reflects enhanced metabolic efficiency and potentially reduced spontaneous physical activity. Research suggests that physical activity levels may decrease during active weight loss but can recover when weight loss is maintained, though the energetic cost of activities remains lower due to reduced body mass [6,26,28,29].

The mechanisms underlying metabolic adaptation involve complex neuroendocrine changes, including reductions in leptin and thyroid hormones that signal decreased energy availability to the hypothalamus. These signals trigger coordinated reductions in energy expenditure across multiple organ systems, representing an integrated physiological response to protect against further energy depletion [23,24,30].

The combined effect of increased appetite-stimulating hormones, decreased satiety signals, and reduced energy expenditure creates a powerful biological pressure toward weight regain that can persist for years after initial weight loss. Understanding these persistent physiological adaptations is essential for developing effective strategies to support long-term weight maintenance and prevent obesity relapse. This recognition has spurred investigation into novel interventions, including ketogenic diets that may counteract or modulate these adaptive responses through distinct metabolic pathways [6,9,25].

The Ketogenic Diet and Metabolic State of Ketosis

The ketogenic diet (KD) is a nutritional intervention distinguished by its very low carbohydrate, moderate protein, and high fat macronutrient composition, designed to induce a metabolic state known as nutritional ketosis. Under standard dietary conditions, glucose derived from carbohydrates serves as the body’s principal energy substrate. However, when carbohydrate intake is drastically reduced, typically to less than 50 grams per day, hepatic glycogen stores become depleted, and the liver increases the conversion of fatty acids into ketone bodies, specifically b-hydroxybutyrate, acetoacetate, and acetone. This elevation in circulating ketone bodies, generally defined as levels above 0.5 mmol/L, marks the onset of nutritional ketosis, enabling ketones to function as an alternative energy source for peripheral tissues and the central nervous system [1,31].

The fundamental mechanisms underlying the effects of the ketogenic diet centres on a shift in. metabolic fuel utilization from glucose toward fatty acids and ketone bodies. In carbohydrate-restricted conditions, insulin secretion declines, enhancing lipolysis and reducing glucose oxidation while simultaneously promoting hepatic ketogenesis. Consequently, tissues that can metabolize ketones, including the brain, cardiac muscle and skeletal muscle, increase uptake of these molecules to sustain cellular energy needs, especially as glucose availability diminishes. This adaptive metabolic switch, which recapitulates aspects of the fasting response, not only preserves energy homeostasis in low-glucose states but also triggers a cascade of neuroendocrine and metabolic adaptation. Of particular interest are the signalling functions of ketone bodies themselves, which interact with pathways related to appetite, inflammation, oxidative stress, and synaptic function, beyond their fundamental energetic role [1,31,32].

Clinically several randomized controlled trials and systematic reviews have demonstrated that ketogenic diets yield reductions in appetite and subjective hunger compared to isocaloric standard diets, especially during periods of active nutritional ketosis. Emerging hormones and central neural circuits, leading to diminished ghrelin levels and favourable changes in satiety peptides such as peptide YY and GLP-1. Patients often report increased fullness and decreased hunger during a ketogenic intervention, which is thought to facilitate adherence and reduce caloric intake independent of conscious restriction. Findings indicate that these appetite suppressing effects are most pronounced when individuals remain in sustained ketosis, potentially offering advantages for weight maintenance and long-term metabolic health compared to higher carbohydrate dietary regimens [33,34,35].

Hormonal and Nutrient Modulators of Appetite in Ketosis

Recent research has illuminated the multi-layered regulatory effects of ketosis on hormonal and nutrient modulators of appetite, underscoring its impact on both peripheral and central pathways. Within the context of a ketogenic diet, key appetite-related hormones including ghrelin, leptin, insulin, amylin, cholecystokinin (CCK), and the ketone body beta-hydroxybutyrate (BHB) exhibit distinctive changes compared to those observed following standard weight loss approaches [36,37].

Figure 2. Effects of Ketone Bodies on AMP-activated Protein Kinase (AMPK) Actions in Different Tissues [36]

Ghrelin, an orexigenic hormone produced in the stomach, typically rises after weight loss and drives increased hunger and food intake, contributing to post-diet relapse. However, in individuals who remain in ketosis following diet-induced weight reduction, the expected elevation in circulating ghrelin is significantly suppressed, which mitigates subjective ratings of appetite and reduces the drive to eat. Leptin, released from adipocytes, declines with fat loss but appears to be lower in ketogenic states, with emerging evidence suggesting that this lower leptin does not provoke compensatory increases in appetite to the same extent as with higher-carbohydrate, lower-fat diets. Insulin, a key hormone for energy metabolism and storage, is consistently reduced during ketosis, reflecting improved glycemic control and enhanced insulin sensitivity, which may facilitate better appetite regulation [1,37,38,39].

Amylin, co-secreted with insulin from the pancreas, has anorexigenic properties, and like leptin, its concentrations are reduced in ketosis; however, the overall effect on satiety appears to be favourable in the ketogenic state. Cholecystokinin (CCK), released in response to dietary fat and protein in the small intestine, is increased by ketosis, exerting a prominent anorexigenic effect and enhancing meal-related satiety. Meanwhile, ketone bodies, most notably BHB serve not just as alternative energy substrates but also interact directly with central appetite pathways, modulating hypothalamic signalling and influencing gut brain crosstalk to lower hunger [36,37,40].

The net result of these hormonal shifts is that ketosis strongly attenuates the rise in hunger and ghrelin observed after conventional weight loss, sustains reductions in subjective appetite, and fosters increased satiety through mechanisms involving CCK, GLP-1, and other gut-derived peptides. Changes in nutrient signalling enable improvements in gut-brain communication, with the vagus nerve acting as a critical conduit for hormonal feedback from the gastrointestinal tract to appetite regulating centres in the hypothalamus. As a result, ketogenic diets may offer a unique advantage for post-diet weight maintenance by dampening the physiological drivers of rebound hunger and enhancing the stability of satiety signals [1,2,33,35].

Evidence from Key Clinical Studies

Summary Of The Pivotal 2013 European Journal Of Clinical Nutrition Study

The pivotal 2013 study published in the European Journal of Clinical Nutrition provided seminal insights into the effects of nutritional ketosis on appetite and hormone dynamics following weight loss. This randomized controlled trial investigated individuals who had completed a period of caloric restriction leading to weight reduction, subsequently stratified into ketotic and non-ketotic groups during the refeeding phase. The authors found a marked suppression of the typical post-diet increase in subjective appetite scores among ketotic patients compared to those on standard refeeding regimens. Critically, the usual surge in hunger signals following weight loss, primarily driven by elevated ghrelin was significantly blunted in those who remained in nutritional ketosis. Furthermore, the study demonstrated that changes in key circulating hormones, including reductions in ghrelin and maintenance of lower insulin and leptin levels, were sustained in the ketotic condition during the refeeding interval, suggesting a durable biological pivot favouring appetite control [37].

Other Landmark Trials And Meta-Analyses Supporting Appetite Control And Fat Loss With Ketogenic Diet

Subsequent clinical studies and meta-analyses have consistently supported the appetite-suppressing and fat loss benefits of ketogenic dietary interventions. Large-scale reviews indicate that, relative to isocaloric higher-carbohydrate diets, ketogenic protocols consistently produce greater reductions in hunger and food intake, with improvements in subjective satiety ratings across diverse populations. Controlled trials have further clarified that these effects are coupled with favourable shifts in gut-derived peptides such as GLP-1 and PYY, stabilization of blood glucose levels, and reductions in insulin demand. Overall, the clinical literature supports the concept that ongoing nutritional ketosis can help counter physiological adaptations driving diet relapse, offering both enhanced appetite regulation and durable fat loss outcomes in obesity management [2,16,23,35,37].

Translational Implications for Obesity Management

Practical Strategies For Applying KD Concepts To Real World Weight Maintenance

Translating the evidence for ketosis-mediated appetite control into practical obesity management requires strategies that address both the biological mechanisms and the real-world challenges of dietary adherence. One of the most promising features of ketogenic diets is their capacity to suppress the compensatory increase in hunger that typically follows weight loss, thereby facilitating long-term weight maintenance without the relentless drive to eat that undermines conventional approaches. To leverage this advantage in clinical practice, healthcare professionals should focus on designing dietary interventions that help individuals achieve and sustain nutritional ketosis during the critical weight maintenance phase, when physiological pressures toward weight regain are at their peak [35,41,42].

Practical implementation begins with education about macronutrient composition, emphasizing a diet consisting of approximately 70-80% fat, 10-20% protein, and less than 5-10% carbohydrates to reliably induce ketosis. Patients benefit from structured meal planning that incorporates nutrient-dense whole foods while restricting high-carbohydrate staples such as grains, legumes, starchy vegetables, and most fruits. Self-monitoring of ketone levels through blood, breath, or urine testing can provide valuable biofeedback to confirm the metabolic state and optimize dietary adherence. Additionally, healthcare providers should promote self-monitoring of food intake through digital applications or food diaries, as this has been consistently associated with improved adherence and weight loss outcomes across dietary interventions [1,35,41,43].

Tailoring ketogenic interventions to individual dietary preferences and nutritional requirements is essential for long-term sustainability. While classical ketogenic diets impose severe restrictions that eliminate entire food groups, more flexible approaches such as modified ketogenic diets with slightly higher protein or carbohydrate allowances may enhance adherence while still maintaining sufficient ketosis for appetite control. Coupling ketogenic nutrition with regular physical activity further amplifies metabolic benefits, including preservation of lean muscle mass and enhancement of insulin sensitivity [35,41,44].

Considerations For Adherence, Cycling Ketosis, And Safety In Long-Term Obesity Treatment

Long-term adherence to strict ketogenic diets remains a significant challenge, with many individuals finding the restrictive nature of the diet difficult to sustain over months to years. Common barriers to adherence include the elimination of culturally important foods, social limitations during dining situations, gastrointestinal side effects such as constipation or diarrhea, and initial “keto flu” symptoms including fatigue, headache, and nausea during the adaptation phase. These obstacles necessitate proactive management strategies, including gradual carbohydrate reduction to ease metabolic adaptation, adequate sodium and electrolyte supplementation to mitigate symptoms, and ongoing behavioural support to navigate social and psychological challenges [41,45,46]

An emerging strategy to improve sustainability is cyclical ketosis or intermittent ketogenic dieting, wherein individuals alternate between periods of strict carbohydrate restriction (typically 5-6 days per week) and planned higher-carbohydrate “refeed” days (1-2 days per week). Proponents suggest that this approach may reduce the burden of continuous restriction, potentially improving psychological well-being and social flexibility while still conferring many of the metabolic benefits of ketosis during the low-carbohydrate phases. However, the current evidence base for cyclical ketosis in humans remains limited, and concerns exist that frequent transitions in and out of ketosis may disrupt metabolic adaptation, promote disordered eating patterns, or result in excess caloric intake during carbohydrate refeeding. Furthermore, water retention and temporary weight fluctuations associated with glycogen replenishment can be psychologically challenging for some individuals. Future research should clarify the minimum duration and degree of ketosis required to achieve appetite suppression and determine optimal protocols for cyclical approaches [41].

Safety considerations for long-term ketogenic diets warrant careful attention, particularly regarding cardiovascular health and lipid metabolism. While short-term studies consistently demonstrate favourable effects on weight loss, triglyceride reduction, HDL cholesterol elevation, and blood pressure improvement, the impact of prolonged high-fat intake, especially saturated fat on low-density lipoprotein (LDL) cholesterol and cardiovascular disease risk remains debated. Some individuals experience substantial increases in LDL cholesterol upon initiating a ketogenic diet, although these elevations often stabilize or decline after several months. Large-scale observational studies suggest that ketogenic dietary patterns may reduce all-cause mortality without increasing cardiovascular mortality, potentially through mechanisms involving improved metabolic health, reduced inflammation, enhanced endothelial function, and favourable alterations in blood pressure and glycemic control. Nonetheless, careful monitoring of lipid profiles, liver function, and kidney function is recommended for individuals following long-term ketogenic diets, and those with pre-existing cardiovascular conditions, familial hyperlipidemia, or genetic predispositions to dyslipidemia should be managed with heightened caution [45,46,47,48,49].

Additional safety considerations include potential nutrient deficiencies due to elimination of food groups rich in vitamins, minerals, and fiber, as well as concerns about bone health and gastrointestinal function during extended ketosis. A well-formulated ketogenic diet should incorporate adequate protein to preserve lean body mass, sufficient micronutrients through careful food selection or supplementation, and appropriate fiber intake to support gut health [41,44,46].

Role Of Exogenous Ketones And Personalized Approaches

The administration of exogenous ketones, typically in the form of ketone salts or ketone esters containing BHB representing a novel strategy to elevate circulating ketone levels independent of strict carbohydrate restriction. This approach may offer a mechanism to mimic the appetite-suppressing effects of nutritional ketosis while allowing consumption of a more balanced and socially acceptable diet aligned with healthy eating guidelines. Studies have demonstrated that oral ketone supplements can rapidly and safely increase blood ketone concentrations, enhance fat oxidation, improve glycemic control, and reduce postprandial glucose excursions in obese individuals [41,50,51,52].

Figure 3. Effects of Ketogenic Diet and Ketone Body Supplementation and Downstream Metabolism [50]

However, the metabolic response to exogenous ketones differs from endogenous ketosis induced by carbohydrate restriction, particularly when ketones are administered in the presence of dietary carbohydrates and insulin. Importantly, exogenous ketones do not stimulate hepatic ketone biosynthesis and therefore do not replicate all aspects of nutritional ketosis. Research examining the impact of exogenous ketone supplementation on weight loss and body composition has yielded mixed results; while some studies report modest improvements in appetite control and glucose metabolism, others find no significant enhancement of weight loss or changes in tissue composition compared to ketogenic diets alone. The optimal dosing, timing, and formulation of exogenous ketones for obesity management remain areas of active investigation [44,51,52,53,54].

A critical frontier in ketogenic nutrition is the development of personalized approach that account for individual genetic, metabolic, and behavioural variability in response to dietary interventions. Genetic polymorphisms affecting lipid metabolism, carbohydrate processing, insulin signalling, mitochondrial function, and ketone utilization can substantially influence the efficacy and safety of ketogenic diets. For example, variants in genes such as APOE, LIPF, GYS2, CETP, and TCF7L2 have been associated with differential responses to low-carbohydrate diets in terms of weight loss, lipid changes, and glycemic control. Individuals carrying the APOE e4 allele may experience more pronounced increases in LDL cholesterol on high-fat diets, necessitating modified fat composition or closer monitoring [49,55,56,57].

Integrating genetic testing, metabolic assessments, and lifestyle factors into clinical decision-making enables healthcare providers to tailor ketogenic interventions to suit each individual’s unique genetic and metabolic profile, potentially enhancing adherence, optimizing health benefits, and minimizing risks. Personalized ketogenic protocols may involve adjusting macronutrient ratios, selecting specific fat sources based on genetic lipid metabolism profiles, timing carbohydrate intake around physical activity, or combining dietary interventions with targeted supplementation. As the field of nutrigenomics advances, precision nutrition approaches incorporating genetic biomarkers and continuous metabolic monitoring potentially augmented by artificial intelligence, hold promise for maximizing the therapeutic potential of ketogenic diets in obesity management and metabolic disease prevention [55,56,57,58].

Sex, Age, and Individual Differences in Response

Emerging research has revealed substantial sex-based differences in the metabolic and hormonal responses to ketogenic diets, with implications for appetite regulation and weight loss efficacy. Preclinical studies in rodent models consistently demonstrate marked sexual dimorphism, wherein male mice on ketogenic diets typically exhibit significant weight loss, reductions in subcutaneous and visceral adipose tissue, improved insulin sensitivity, and elevated circulating concentrations of fibroblast growth factor 21 (FGF21), a key metabolic hormone involved in energy homeostasis. In contrast, female mice often show attenuated or even paradoxical responses, including weight gain, increased perigonadal fat accumulation, impaired glucose tolerance, and reduced insulin sensitivity when subjected to identical ketogenic protocols. These differential effects appear to be mediated, at least in part, by sex hormones, particularly estrogen, which exerts protective metabolic effects and influences ketone metabolism [19,59,60,61].

The modulatory role of estrogen is further supported by experiments demonstrating that oophorectomy (surgical removal of ovaries) in female mice reverses the unfavorable metabolic outcomes of ketogenic diets, resulting in fat loss and improved glycemic control comparable to that observed in males. Conversely, administration of estrogen or estradiol to male mice on ketogenic diets prevents the accumulation of senescent cells and oxidative stress, effects that are otherwise characteristic of ketosis in males. When female mice are treated with tamoxifen, a selective estrogen receptor modulator that blocks estrogen signalling, they exhibit increased oxidative stress and cellular senescence markers similar to males, strongly implicating estrogen as a critical variable in the response to ketogenic nutrition [19,61].

Beyond sex differences, age-related variations in appetite-regulating hormones significantly influence hunger, satiety, and energy intake across the lifespan. Older adults consistently demonstrate higher fasting and postprandial concentrations of anorexigenic (appetite-suppressing) hormones, including cholecystokinin (CCK), leptin, insulin, and peptide YY (PYY), compared to younger individuals. These hormonal elevations are associated with the well-characterized phenomenon of “anorexia of aging,” which describes reductions in appetite and voluntary energy intake that occur in 15-30% of independently living older adults and are associated with increased risk of frailty, sarcopenia, disability, and mortality. Conversely, younger adults tend to exhibit lower baseline concentrations of satiety hormones and higher circulating ghrelin, correlating with greater hunger drive and higher energy intake. These age-related differences in hormonal profiles have important implications for the design and implementation of ketogenic dietary interventions, as the appetite-suppressing effects of ketosis may be more pronounced in younger individuals with lower baseline satiety signalling, whereas older adults may experience diminished benefits or require modified protocols to preserve muscle mass and nutritional adequacy [58,62].

Sex-specific patterns in appetite hormones during ketogenic weight loss have also been documented in human clinical trials. In a study examining progressive changes in appetite during ketogenic weight reduction, females exhibited overall higher fullness scores and higher basal and postprandial concentrations of acylated ghrelin (AG), while males reported higher hunger, greater desire to eat, and higher prospective food consumption (PFC) ratings. Notably, males experienced a substantially larger absolute energy deficit due to higher baseline energy requirements, which may have contributed to the observed sex differences in subjective appetite ratings. Investigations into the impact of ketosis on appetite-related gut hormones revealed that ketosis appears to confer a greater beneficial effect on glucagon-like peptide-1 (GLP-1) secretion in females compared to males, suggesting sex-specific mechanisms of appetite regulation in the ketotic state [16].

Observed Heterogeneity In Studies; Implications For Personalized Medicine

Despite the growing body of clinical evidence supporting the efficacy of ketogenic diets for weight loss and appetite control, substantial heterogeneity exists across studies in terms of individual responses, adherence rates, metabolic outcomes, and hormonal adaptations. Meta-analyses examining the variability in weight loss responses to low-carbohydrate and ketogenic diets have reported pooled standard deviations for individual responses ranging from 1.4 kg, with wide 95% prediction intervals spanning from -6.3 to 10.4 kg, indicating that some individuals experience substantial weight loss while others may gain weight on identical interventions. This pronounced inter-individual variability cannot be attributed solely to differences in adherence or caloric intake, but rather reflects complex interactions among genetic factors, metabolic phenotypes, gut microbiome composition, hormonal status, lifestyle variables, and environmental influences [35,63,64,65,66,67].

Genetic polymorphisms affecting key metabolic pathways including lipid metabolism, carbohydrate processing, insulin signalling, mitochondrial function, and ketone utilization have been shown to substantially modulate individual responses to ketogenic diets. For instance, genetic variants in genes such as APOE, LIPF, GYS2, CETP, and TCF7L2 are associated with differential weight loss, lipid profile changes, and glycemic responses to low-carbohydrate dietary interventions. Carriers of the APOE e4 allele may experience more pronounced increases in LDL cholesterol when consuming high-fat diets, necessitating individualized macronutrient modifications and closer cardiovascular monitoring. Additionally, research has identified sex-specific genetic architectures in response to ketogenic diets, with certain genetic markers explaining 22.8% of the variation in males but only 5.9% in females, further underscoring the importance of considering sex as a biological variable in precision nutrition approaches [49,56,57,68].

The observed heterogeneity extends beyond genetic factors to encompass differences in baseline metabolic health, body composition, insulin sensitivity, gut microbiota profiles, and psychosocial factors that influence adherence and behavioural responses to dietary restriction. For example, individuals with higher baseline insulin resistance and metabolic dysfunction may experience greater improvements in glycemic control and weight loss on ketogenic diets compared to metabolically healthy individuals. Conversely, some individuals may exhibit minimal metabolic benefits or adverse lipid changes, highlighting the need for personalized assessment and monitoring [49,51,65,66,69].

These findings have profound implications for the emerging field of precision nutrition, which seeks to tailor dietary interventions to the unique characteristics of each individual, integrating genetic, phenotypic, metabolic, lifestyle, and environmental data to optimize health outcomes. In the context of ketogenic diets for obesity management, precision nutrition approaches may involve genetic testing to identify individuals most likely to benefit from ketogenic interventions, continuous metabolic monitoring using wearable devices and ketone sensors to ensure sustained ketosis, personalized macronutrient prescriptions based on lipid metabolism genotypes, and integration of gut microbiome analysis to predict and enhance dietary responses. Artificial intelligence and machine learning algorithms can further refine these approaches by analysing complex multidimensional datasets to generate individualized dietary recommendations that maximize efficacy while minimizing risks [65,68,69,70].

As the scientific understanding of inter-individual variability in ketogenic diet response continues to advance, the integration of precision nutrition principles into clinical practice holds great promise for improving adherence, optimizing metabolic outcomes, and personalizing obesity treatment strategies to meet the unique needs of diverse patient populations [65,68,71].

Limitations, Controversies, and Future Directions

Gaps In Current Research: Sustainability, Cardiometabolic Risk, Behavioural Factors

Despite accumulating evidence supporting the efficacy of ketogenic diets for appetite suppression and short-term weight loss, significant gaps remain in our understanding of their long-term sustainability, cardiometabolic safety, and behavioural determinants of adherence. The highly restrictive nature of ketogenic nutrition, requiring near elimination of entire food groups including grains, legumes, most fruits, and starchy vegetables poses formidable challenges to sustained adherence, with longitudinal studies consistently documenting high dropout rates and difficulty maintaining strict carbohydrate restriction beyond 6-12 months. Many participants struggle with the social isolation, meal preparation burden, gastrointestinal side effects, and psychological distress associated with prolonged dietary restriction, resulting in premature discontinuation or non-adherence in 40-60% of individuals in clinical trials [45,46,63,72,73,74].

The lack of standardized definitions for ketogenic diets across studies with varying carbohydrate thresholds ranging from less than 20 grams to less than 50 grams per day, and inconsistent criteria for measuring and confirming nutritional ketosis, further complicates interpretation of the literature and limits the ability to draw definitive conclusions about long-term efficacy. Additionally, most ketogenic diet trials have been conducted over relatively short durations, typically 8-24 weeks, with few rigorously controlled studies extending beyond one year. This dearth of long-term data leaves critical questions unanswered regarding the durability of appetite suppression, the sustainability of weight loss maintenance, the persistence of metabolic benefits, and the emergence of potential adverse effects with prolonged adherence [63,72,73].

Cardiometabolic risk associated with long-term ketogenic diets remains one of the most contentious areas of debate. While short-term studies consistently demonstrate favourable improvements in triglycerides, HDL cholesterol, blood pressure, and glycemic control, concerns persist regarding elevations in low-density lipoprotein cholesterol (LDL-C) observed in a subset of individuals. Case series have documented dramatic increases in LDL cholesterol, in some instances exceeding 200 mg/dL among individuals following ketogenic diets, with average LDL elevations of 187 mg/dL (a 245% increase) reported in patients adhering to the diet for an average of 12.3 months. These elevations reversed upon cessation of the ketogenic diet, with LDL levels decreasing by an average of 174 mg/dL (a 220% decrease). While some research suggests that these LDL elevations may not translate to increased cardiovascular risk in lean, metabolically healthy individuals, particularly when accompanied by improvements in other cardiometabolic markers, the long-term implications remain uncertain and warrant cautious monitoring [47,75,76].

Individuals with genetic predispositions to cholesterol metabolism dysregulation, including those carrying APOE e4 alleles or other lipid-related genetic variants, may experience disproportionate elevations in LDL cholesterol and potentially heightened cardiovascular risk when consuming high-fat diets. The complex relationship between dietary fat composition (saturated versus unsaturated), circulating cholesterol levels, lipoprotein particle size and oxidation status, and atherosclerotic cardiovascular disease risk necessitates individualized assessment and ongoing surveillance [47,57,75,77].

Behavioural and psychological factors influencing ketogenic diet adherence represent another critical knowledge gap. Personality characteristics such as conscientiousness, lower emotional eating tendencies, and openness to experience have been associated with better dietary adherence, while depression, anxiety, and low self-efficacy predict poor adherence and premature discontinuation. The relationship between ketogenic diets and mental health outcomes remains incompletely characterized, with emerging evidence suggesting potential benefits for mood and anxiety in some populations, but also risks of disordered eating patterns, social isolation, and psychological distress related to dietary restriction. The majority of preclinical studies examining behavioural effects of ketosis have focused on cognition and depressive-like behaviours, with relatively few addressing anxiety-related behaviours, social behaviours, or appetite regulation specifically. This gap in behavioural research limits our ability to predict which individuals are most likely to succeed with long-term ketogenic interventions and underscores the need for comprehensive psychosocial assessments as part of personalized dietary counselling [45,74,78,79].

New Frontiers: Integrating Biomarkers, AI-Assisted Diet Planning, And Continuous Metabolic Monitoring

The future of ketogenic nutrition for obesity management lies in the integration of advanced technologies that enable precision nutrition approaches tailored to individual metabolic profiles, genetic predispositions, and real-time physiological responses. Artificial intelligence (AI) and machine learning algorithms are rapidly transforming the field of personalized nutrition by analysing complex, multimodal datasets including genetic information, metabolic biomarkers, gut microbiome composition, dietary intake patterns, and wearable sensor data to generate individualized dietary recommendations that optimize health outcomes while minimizing risks [65,80,81,82].

AI-driven nutrition platforms such as ZOE and DayTwo exemplify the practical implementation of precision nutrition, leveraging machine learning algorithms integrated with comprehensive biological data, including gut microbiome profiles, postprandial glycemic responses, and blood lipid measurements, to generate personalized dietary recommendations. These platforms utilize supervised learning models, including multilayer perceptrons and long short-term memory networks, to predict individual responses to specific foods and macronutrient compositions, enabling adaptive dietary planning that can be continuously refined based on real-time feedback. Deep learning techniques, particularly convolutional neural networks paired with computer vision, have achieved classification accuracies exceeding 90% for food image recognition and nutrient estimation, facilitating automated dietary assessment and adherence monitoring through smartphone applications [81,82].

The integration of continuous metabolic monitoring technologies represents another transformative frontier for optimizing ketogenic interventions. Continuous glucose monitors (CGMs), which have achieved widespread adoption in diabetes management with global sales exceeding 1.6 billion dollars in 2020, provide real-time data on glucose dynamics, enabling individuals to observe the immediate glycemic impact of dietary choices and make informed adjustments. Over-the-counter CGM systems such as Stelo and Lingo have recently received regulatory approval for use by consumers without diabetes who seek to enhance metabolic health and wellness, expanding access to continuous metabolic feedback beyond clinical populations [83,84].

Emerging continuous ketone monitoring (CKM) technologies offer complementary insights into ketone dynamics, surpassing traditional single-point testing methods by providing real-time, continuous measurement of beta-hydroxybutyrate (BHB) concentrations through wearable sensors similar to CGMs. These devices employ electrochemical sensors that detect BHB in interstitial fluid, with studies demonstrating feasibility and accuracy in both clinical and personal-use settings. The integration of CGM and CKM data within a single multi-sensor platform, augmented by artificial intelligence algorithms, has the potential to generate a highly integrated metabolic picture that captures glucose-ketone dynamics, enabling more precise titration of macronutrient intake to achieve and maintain optimal nutritional ketosis while preserving glycemic stability [84,85].

Future developments in continuous metabolic monitoring may incorporate additional biomarkers of appetite regulation, including circulating concentrations of ghrelin, GLP-1, PYY, amino acids, lipid mediators, and other metabolites that reflect satiety status and energy balance. Research has identified that specific amino acids and their derivatives exhibit differential associations with hunger and satiety sensations and may serve as biomarkers of appetite under certain conditions. The integration of these biomarker data with wearable sensor outputs, genetic profiles, and AI-driven predictive models could enable highly personalized dietary interventions that dynamically adjust macronutrient composition in response to real-time metabolic and appetite signals, optimizing both weight loss efficacy and long-term adherence [85,86].

Summary Of Unanswered Questions And Next Steps

Numerous critical questions remain to be addressed through future research to fully realize the therapeutic potential of ketogenic diets for obesity management and metabolic disease prevention. Key unanswered questions include: What is the optimal duration and degree of nutritional ketosis required to achieve sustained appetite suppression and prevent weight regain? Can cyclical or intermittent ketogenic approaches provide comparable metabolic benefits while improving adherence and social acceptability? What genetic, metabolic, and behavioural phenotypes predict individual responsiveness to ketogenic interventions, and how can this information be leveraged to personalize dietary prescriptions? What are the long-term cardiovascular outcomes associated with sustained ketogenic nutrition, particularly in individuals with genetic predispositions to dyslipidemia? How do ketogenic diets influence gut microbiome composition, and what role does the microbiome play in mediating appetite regulation and metabolic adaptations during ketosis? [72,87]

To address these questions, future research should prioritize large-scale, long-term randomized controlled trials with durations extending beyond one year, incorporating comprehensive assessments of adherence, body composition, metabolic markers, cardiovascular outcomes, and quality of life. Studies should employ standardized definitions of ketogenic diets and validated methods for confirming nutritional ketosis, including measurement of blood ketone concentrations rather than relying solely on dietary recall or urine ketone testing. Integration of precision nutrition approaches that incorporate genetic testing, metabolic phenotyping, gut microbiome analysis, and continuous metabolic monitoring will enable identification of individual response patterns and optimization of personalized dietary interventions [65].

Additionally, research examining behavioural and psychological factors influencing adherence, including the development and validation of predictive models for identifying individuals most likely to succeed with ketogenic interventions, will inform targeted counselling and support strategies. Investigation of novel biomarkers of appetite regulation during ketosis, including metabolomic and lipidomic profiling, may elucidate mechanisms underlying appetite suppression and identify therapeutic targets for pharmacological or nutraceutical interventions that mimic the benefits of ketosis without requiring strict dietary restriction. Finally, examination of exogenous ketone supplementation as a strategy to augment or replace dietary ketosis, including dose-response relationships, optimal timing, and formulation characteristics, may expand the therapeutic toolkit for obesity management while addressing adherence barriers associated with restrictive diets [86].

As the scientific community continues to advance our understanding of ketosis-mediated appetite control through rigorous investigation and technological innovation, the integration of precision nutrition principles with AI-assisted planning and continuous metabolic monitoring holds great promise for breaking the hunger cycle and supporting durable weight loss maintenance in the battle against obesity and metabolic disease [80].

Conclusion: Harnessing Ketosis for Durable Appetite Control and Weight Maintenance

A robust body of clinical and mechanistic evidence now supports the therapeutic role of nutritional ketosis in breaking the hunger cycle and advancing durable weight maintenance. Ketogenic diets suppress the compensatory increases in appetite and hunger hormones commonly observed after weight loss, most notably attenuating the rise in ghrelin and stabilizing satiety peptides such as GLP-1 and CCK. This neuroendocrine shift mitigates subjective hunger and enhances fullness, effects substantiated by pivotal trials and meta-analyses that demonstrate superior appetite control and sustained fat loss compared to standard or higher carbohydrate dietary regimens.

These effects persist as long as nutritional ketosis is maintained, with clinical studies revealing that circulating hunger hormones remain lower and satiety signals higher throughout the critical weight maintenance phase. Importantly, this mechanistic benefit is not just limited to isolated hormone changes, ketogenic diets induce a global shift in energy metabolism, lowering insulin, facilitating lipolysis and driving hepatic ketogenesis, which together promote metabolic flexibility and glycemic stability. Ketone bodies themselves exert direct effects on hypothalamic appetite centres and gut-brain signalling, further reinforcing appetite suppression and satiety.

Prospects for KD-based strategies in obesity management are promising. The incorporation of ketogenic nutrition during weight maintenance may protect against physiological drivers of relapse, offering a pathway to improved adherence and lasting metabolic health. Innovations such as cyclical ketosis, exogenous ketone supplementation, and precision nutrition approaches using genetic, metabolic, and behavioural profiles are expanding the toolkit for personalized obesity treatment. Advanced monitoring including continuous metabolic and ketone measurement, and AI-assisted dietary planning can further refine these strategies, making them more adaptive, sustainable, and patient-centred.

In summary, harnessing the state of ketosis offers an evidence-based foundation for durable appetite control and weight loss maintenance. As research advances and technology enables increasingly individualized nutritional guidance, KD-based interventions hold significant promise for breaking the hunger cycle and supporting long-term metabolic health.

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