In recent years, there has been escalated interest in the use of ketogenic diets as a noninvasive tool for weight loss and the management of obesity and its comorbidities. This is due to the long track record of safety of ketogenic diets, the absence of widespread adverse events, and its potential to reduce the health and economic burden associated with these diseases . Ketogenic diets popularity can also be attributed to their ability to induce rapid weight loss without the concomitant increase in appetite otherwise seen when weight loss is induced by non-ketogenic diets . In fact, individuals undergoing ketogenic diets have reported feeling less hungry in the fasted state, and at times, fuller after a meal [1,3▪,4▪]. Studies have also shown that while under ketosis, the increase in hunger feelings and ghrelin secretion, which is often seen with diet-induced weight loss, is suppressed [5–7]. The ability for ketogenic diets to suppress appetite is of great clinical relevance, given the vital role appetite plays in body weight regulation. An upregulation of ghrelin secretion, paralleled by increased feelings of hunger and desire to eat, is often reported in response to diet induced weight loss [7,8]. The increased feelings of hunger in response to diet-induced weight loss can be seen as the most commonly reported side effect of dieting and is likely to compromise treatment adherence overtime and reduce weight loss outcomes.
Due to the promising prospect of ketogenic diets improving adherence to weight loss interventions, a better understanding of the relationship between ketogenic diets and appetite is warranted. This narrative review aims to elucidate the current evidence on the effect of ketogenic diets on appetite regulation, with special emphasis on studies published over the last 2 years.
KETOSIS AND KETOGENIC DIETS
During periods of fasting, or when carbohydrates (CHO) are in short supply, the ketone bodies acetoacetate, βeta-hydroxybutyrate (βHB) and acetate are synthesized from free fatty acids, as an alternative source of energy. The absence of appreciable dietary CHO as a source of energy causes a reduction in insulin plasma concentration and a depletion of glycogen stores, thereby reducing lipogenesis and the accumulation of fat. As glycogen stores become depleted, ketogenesis increases with the production of ketone bodies in the mitochondria of liver cells, via the hepatic β-oxidation of free fatty acids . The metabolic state of nutritional ketosis is usually defined as a plasma βHB concentration ≥ 0.3 mmol/l , even though a threshold of ≥ 0.5 mmol has also been used .
Despite the widespread attention and use of ketogenic diets in recent years, there is no clear consensus in the literature as to what constitutes a ketogenic diets, as the magnitude of CHO restriction necessary to induce ketosis has been loosely defined [4▪,10]. The various terms used in the literature for ketogenic diets include, but are not limited to, ‘low carbohydrate diet’ (LCD), ‘ketogenic low carbohydrate diet’ (KLCD), ‘very low energy diet’ (VLED), and ‘very-low calorie ketogenic diet’ (VLCKD). LCDs prescriptions provide 50 – 150 g/day of CHO and energy intake is usually ad libitum; KLCDs provide < 50 g/day of CHO with ad libitum consumption of fat and protein; VLEDs provide less than 800 kcal/day, with a CHO content ranging between 50 and 150 g /day, 15 g/day of fat, and protein intake corresponding to 0.8–1.5 g/kg of ideal body weight. VLCKDs provide less than 800 kcal/day, limit CHO intake to 30–50 g/day, and provide 0.8–1.5 g of protein /kg of body weight/day [2,10].
IMPACT OF KETOGENIC DIETS ON APPETITE
Modifications in the macronutrient composition of diets or food components have been shown to affect hormones, metabolic pathways, gene expression, and appetite control . Several studies have provided evidence for the appetite suppressant effect of ketogenic diets and shown that for as long as participants are in a state of ketosis, appetite does not increase, despite weight loss . It has been consistently shown by our research group [3▪,5,6,12] and others  that under ketogenic conditions, feelings of hunger, measured using validated visual analogue scales (VASs), do not increase, even when massive weight loss is achieved (up to 17% or initial body weight) . Studies where hunger feelings have been evaluated through other methods, such as the Three Factor Eating Questionnaire , the Food Craving Questionnaire , nonvalidated questionnaires [16,17,18], semi-structured interviews,  and case reports [20,21] have also confirmed that ketogenic diets are associated with diminished or absent feelings of hunger, a reduced desire to eat and decreased overall appetite.
From our knowledge, all the available evidence shows that the secretion of the hunger hormone ghrelin, which is upregulated in response to diet-induced weight loss , is blunted under ketogenic conditions [2,3▪,5,6,12,15,16]. Moreover, once participants are no longer in ketosis, upon refeeding and re-introduction of CHO, the expected surge in ghrelin secretion and hunger feelings above baseline levels is seen [5,12]. The effect of ketogenic diets on the release of satiety hormones, namely cholecystokinin (CCK), glucagon-like peptide-1 (GLP-1) and peptide YY, remains unfortunately inconclusive. Our group has found no changes in the postprandial release of these satiety peptides with a 17% weight loss induced using VLED, independently of the participants being in or out of ketosis .
Whether appetite responses to ketosis differ between males and females is yet to be fully determined. However, our research group found that the basal and postprandial secretion of GLP-1 in response to weight loss induced by a VLED was modulated by sex, with a decrease in basal GLP-1 concentrations seen only in males, and an increase in postprandial concentration of GLP-1 happening only in females .
The threshold of nutritionally induced ketosis needed to achieve appetite suppression using ketogenic diets has yet to be determined. However, the results from the systematic review and meta-analysis performed by Gibson and colleagues indicate that a restriction of CHO below 50 g/day does not appear to be necessary. This raises the question of whether such a restriction should be applied in ketogenic diets, because the severity of the CHO restriction is counterintuitive to healthy eating recommendations . Entire core food groups, such as whole grains, legumes, reduced-fat dairy, fruits, and vegetables need to be severely constrained or eliminated due to the need to significantly reduce CHO intake [2,4▪]. This restriction and elimination may have a negative impact on bone health and increase the risk of developing certain types of cancer and cardiovascular disease [3▪,22,23]. Furthermore, in addition to the CHO restriction, fiber intake is also reduced in ketogenic diets and likely explains why constipation is one of the most commonly reported side effects of these diets .
Given that high amounts of circulating ketones have been seen in participants who followed diets with a CHO intake of up to 192 g/day [4▪], a greater allowance of CHO in ketogenic diets might and should be considered in future formulations. The literature on this topic seems to suggest that 100 g/day of CHO should be the cut off for ketogenic diets [4▪,10]. A more liberal CHO allowance can, for instance, enable the incorporation of CHO-rich vegetables that are higher in fiber content pivotal to alleviate constipation in those undergoing ketogenic diets and allow for the consumption of calcium-containing dairy products with fortified vitamin D and calcium to hinder bone loss that has been seen as a long-term side effect of VLED .
Harvey and colleagues reported recently that eucaloric diets containing up to 25% total energy from CHO can result in mean ßHB ≥ 0.5 mmol/L, with no clinical relevant differences in symptoms of CHO withdrawal between diets containing from 5% to 25% total energy from CHO .
MECHANISMS BY WHICH KETOGENIC DIETS SUPPRESS APPETITE
The exact molecular mechanisms by which ketogenic diets suppress appetite remain to be established [4▪]. Paoli and colleagues have summarized the current knowledge of the relationship between ketosis, ketogenic diets and appetite control, and outlined the complexity that arises from the contradictory role ketosis seems to play on both anorexigenic and orexigenic signals . This research group has also suggested that the ability of ketogenic diets to suppress appetite may be mediated by changes in the gut microbiota, namely a decrease in alpha diversity and richness of the microbiome . Despite the difficulties arising from the variability of microbiome composition among individuals, there is speculation that the low CHO and fiber content in ketogenic diets may lead to a decrease in the concentration of bifidobacteria, butyrate producing bacteria, and overall butyrate availability [4▪,10].
Nevertheless, it is believed that ketosis is the most likely culprit for the appetite suppressant effects seen under KD, as the absence of increased ghrelin secretion and hunger feelings which accompanies weight loss has been shown to last only for as long as participants are ketotic [5,12]. To better comprehend the role of ketones on appetite suppression, correlation analyses have been performed by several studies between the plasma concentration of βHB measured in a fasted state and changes in markers of appetite in participants who have lost weight through ketogenic diets. Our group has reported a negative association between βHB and changes in basal ghrelin concentrations and a positive association between βHB and changes in postprandial GLP-1 and CCK concentrations [3▪]. Unexpectedly, these associations were only seen in females, which could be due to the fact that women were more ketotic (as seen by a higher βHB plasma concentration) than men in response to the VLED [3▪]. Another interesting finding was that despite the previously described association between βHB and the secretion of both orexigenic and anorexigenic hormones, no association was seen between βHB and subjective feelings of appetite [3▪]. This is, however, not in line with the study by Castro and colleagues, who reported a negative correlation between βHB and hunger and desire to eat measured in fasting . The reported findings described above offer additional supporting evidence for the role ketosis plays in modulating appetite [4▪]. The evidence of these associations, however, cannot be used to determine whether elevated ketone levels directly lead to the suppression of appetite seen with ketogenic diets. Despite the fact that, at present, no evidence for a cause-effect relationship between elevated ketones seen during ketogenic diets and appetite suppression exists, studies using exogenous ketones may provide important cues regarding causality.
Exogenous ketones, in the form of commercially available supplements, provide a unique opportunity to investigate the effects of nutritional induced ketosis on appetite. The impact of ketone supplements (esters and salts) on appetite has been recently summarized and the available evidence points to exogenous ketones being able to reduce food intake and/or appetite [4▪].
In what is seen as the landmark paper in this field, Stubbs and colleagues reported decreased ghrelin plasma concentrations and perceived hunger and desire to eat, as a result of elevated ketones following the consumption of an exogenous ketone, compared with the consumption of an isocaloric dextrose beverage, in normal weight-individuals [25▪▪]. In a recently published study, Poffé and colleagues reported that the ingestion of oral ketone esters during endurance training overload for 3 weeks did not have an effect on fasting ghrelin serum concentrations or feelings of hunger measured using VAS . However, it needs to be taken into account that no significant differences were seen in blood ßHB fasting concentration between the ketone ester and the control condition and peak ßHB reached only 0.35 mM, which can contribute, at least partially, to the negative outcomes. In another study by the same group, but this time an acute intervention, it was found that the ingestion of oral ketone esters early during a simulated cycling race reduced feelings of hunger and desire to eat, measured using VAS, and ghrelin serum concentrations, when compared with a control supplement . In another study recently published, Rittig and colleagues reported a similar increase in ßHB blood concentration (peak 1.4 mM) after an isoketonemic dose of exogenous ketones given either orally or intravenously. Moreover, no differences in GLP-1 secretion or appetite sensations were seen between conditions, despite the oral ketone supplement resulting in increased CCK and insulin concentrations . Overall, the majority of the available evidence points to exogenous ketones having the ability to suppress feelings of appetite and reduce ghrelin secretion, suggesting that ketone bodies might have a direct effect on appetite.
The available evidence shows that ketogenic diets have the ability to yield significant weight loss while blunting the increase in ghrelin secretion and feelings of hunger that accompany diet-induced weight loss. Studies using exogenous ketones also point out in the same direction. The exact mechanisms by which ketogenic diets suppress appetite remain to be fully determined, but evidence from investigations employing exogenous ketones points to a direct effect of ketones on appetite.
Future studies should evaluate the possibility of increasing CHO allowances in ketogenic diets in order to alleviate their adverse effects on gastrointestinal and bone health. The complexity of the physiological mechanisms involved in the appetite suppressant effect of ketogenic diets also warrants further investigation, particularly the molecular mechanisms by which βHB modulates ghrelin secretion. Finally, given that the majority of the studies have only assessed the acute effects of exogenous ketones on appetite, more research investigating their long-term efficacy and safety is needed.
Financial support and sponsorship
This work was supported by the Norwegian University of Science and Technology (NTNU) and the Liaison Committee for Education, Research, and Innovation in Central Norway in partnership with NTNU.
Conflicts of interest
There are no conflicts of interest.
REFERENCES AND RECOMMENDED READING
Papers of particular interest, published within the annual period of review, have been highlighted as:
▪ of special interest
▪▪ of outstanding interest
1. Ludwig DS. The ketogenic diet: evidence for optimism but high-quality research needed. J Nutr 2020; 150:1354–1359.
2. Gibson AA, Seimon RV, Lee CMY, et al. Do ketogenic diets really suppress appetite? A systematic review and meta-analysis. Obes Rev 2015; 16:64–76.
3▪. Martins C, Nymo S, Truby H, et al. Association between ketosis
and changes in appetite markers with weight loss following a very low-energy diet. Obesity 2020; 28:2331–2338.
4▪. Deemer SE, Plaisance EP, Martins C. Impact of ketosis
on appetite regulation-a review. Nutr Res 2020; 77:1–11.
5. Nymo S, Coutinho SR, Jorgensen J, et al. Timeline of changes in appetite during weight loss with a ketogenic diet. Int J Obes (Lond) 2017; 41:1224–1231.
6. Lyngstad A, Nymo S, Coutinho SR, et al. Investigating the effect of sex and ketosis
on weight-loss-induced changes in appetite. Am J Clin Nutr 2019; 109:1511–1518.
7. Iepsen EW, Lundgren J, Holst JJ, et al. Successful weight loss maintenance includes long-term increased meal responses of GLP-1 and PYY3-36. Eur J Endocrinol 2016; 174:775–784.
8. Nymo S, Coutinho S, Eknes P, et al. Investigation of the long-term sustainability of changes in appetite after weight loss. Int J Obes (Lond) 2018; 42:1489–1499.
9. Harvey CJdC, Schofield GM, Zinn C, Thornley S. Effects of differing levels of carbohydrate restriction on mood achievement of nutritional ketosis
, and symptoms of carbohydrate withdrawal in healthy adults: a randomized clinical trial. Nutrition: X 2019; 2:100005.
10. Di Rosa C, Lattanzi G, Taylor SF, et al. Very low calorie ketogenic diets in overweight and obesity treatment: Effects on anthropometric parameters, body composition, satiety, lipid profile and microbiota. Obes Res Clin Pract 2020; 14:491–503.
11. Freire RH, Alvarez-Leite JI. Appetite control: hormones or diet strategies? Curr Opin Clin Nutr Metab Care 2020; 23:328–335.
12. Coutinho SR, With E, Rehfeld JF, et al. The impact of rate of weight loss on body composition and compensatory mechanisms during weight reduction: a randomized control trial. Clin Nutr 2018; 37:1154–1162.
13. Nymo S, Coutinho SR, Jorgensen J, et al. Timeline of changes in appetite during weight loss with a ketogenic diet. Int J Obes 2017; 41:1224–1231.
14. Anguah K-B, Syed-Abdul MM, Hu Q, et al. Changes in food cravings and eating behavior after a dietary carbohydrate restriction intervention trial. Nutrients 2020; 12:52.
15. Castro AI, Gomez-Arbelaez D, Crujeiras AB, et al. Effect of a very low-calorie ketogenic diet on food and alcohol cravings, physical and sexual activity, sleep disturbances, and quality of life in obese patients. Nutrients 2018; 10:1348.
16. Mohorko N, Černelič-Bizjak M, Poklar-Vatovec T, et al. Weight loss, improved physical performance, cognitive function, eating behavior, and metabolic profile in a 12-week ketogenic diet in obese adults. Nutr Res 2019; 62:64–77.
17. Choi HR, Kim J, Lim H, Park YK. Two-week exclusive supplementation of modified ketogenic nutrition drink reserves lean body mass and improves blood lipid profile in obese adults: a randomized clinical trial. Nutrients 2018; 10:1895.
18. De Toledo FW, Grundler F, Bergouignan A, et al. Safety, health improvement and well being during a 4 to 21-day fasting period in an observational study including 1422 subjects. PLoS ONE 2019; 14:e0209353.
19. Hafez Griauzde D, Saslow L, Patterson K, et al. Mixed methods pilot study of a low-carbohydrate diabetes prevention programme among adults with prediabetes in the USA. BMJ Open 2020; 10:e033397.
20. Anekwe CV, Chandrasekaran P, Stanford FC. Ketogenic diet-induced elevated cholesterol, elevated liver enzymes and potential nonalcoholic fatty liver disease. Cureus 2020; 12:e6605.
21. Carmen M, Safer DL, Saslow LR, et al. Treating binge eating and food addiction symptoms with low-carbohydrate Ketogenic diets: a case series. J Eat Disord 2020; 8:2.
22. Seimon RV, Wild-Taylor AL, Keating SE, et al. Effect of weight loss via severe vs moderate energy restriction on lean mass and body composition among postmenopausal women with obesity: the TEMPO diet randomized clinical trial. JAMA Netw Open 2019; 2:e1913733.
23. Brehm BJ, Seeley RJ, Daniels SR, D’Alessio DA. A randomized trial comparing a very low carbohydrate diet and a calorie-restricted low fat diet on body weight and cardiovascular risk factors in healthy women. J Clin Endocrinol Metab 2003; 88:1617–1623.
24. Paoli A, Mancin L, Bianco A, et al. Ketogenic diet and microbiota: friends or enemies? Genes (Basel) 2019; 10:534.
25▪▪. Stubbs BJ, Cox PJ, Evans RD, et al. A ketone ester drink lowers human ghrelin and appetite. Obesity (Silver Spring) 2018; 26:269–273.
26. Poffé C, Ramaekers M, Van Thienen R, Hespel P. Ketone ester supplementation blunts overreaching symptoms during endurance training overload. J Physiol 2019; 597:3009–3027.
27. Poffé C, Ramaekers M, Bogaerts S, Hespel P. Exogenous ketosis
impacts neither performance nor muscle glycogen breakdown in prolonged endurance exercise. J Appl Physiol (1985) 2020; 128:1643–1653.
28. Rittig N, Svart M, Thomsen HH, et al. Oral D/L-3-hydroxybutyrate stimulates cholecystokinin and insulin secretion and slows gastric emptying in healthy males. J Clin Endocrinol Metab 2020; 105:dgaa483.