According to recent Harvard models, 50% of the children today are likely to be obese by the age of 35 years . As scientists try to determine the most effective strategies to combat the obesity epidemic, many studies have emerged that compare the health outcomes of different diets. A recent meta-analysis of seven random-controlled trials using diazoxide or octreotide for suppressing insulin secretion in obese patients found that it led to reduced body weight, fat mass, while maintaining lean mass . However, the cost of artificially reducing insulin levels was an increase in blood glucose levels. While these studies seem promising as an indicator of biomarkers that can stimulate weight loss, it seems more logical to help patients achieve lower insulin levels via changes to their diet. The reduction of carbohydrate intake naturally reduces blood glucose levels, thus reducing insulin as a result. Many studies have now demonstrated that the ketogenic diet reduces both blood glucose and insulin levels [,3,4]
A study conducted by Fumagalli et al. [5 analyzed the genetic profiles of patients and looked at the impacts on metabolism. They specifically looked at human CHC22 clathrin, which plays a central role in intracellular traffic of insulin-responsive glucose transporter 4 (GLUT4). The GLUT4 pathway is the dominant mechanism used by humans to remove glucose from the circulating blood after a meal. They found two major gene variants, one which is more frequent in farming populations than in hunter-gatherers. Hunter-gatherers have the gene that allows GLUT4 to be sequestered more effectively and thus have an inherent increased risk of insulin resistance. It is hypothesized that as humans became farmers and increased glucose in the diet, it was beneficial for the blood sugar to be lowered more easily with the newer form of CHC22. Thus, people with different forms of CHC22 are likely to differ in their ability to clear blood sugar after a meal. The people with the form that allows blood sugar levels to remain elevated could eventually lead to diabetes in the face of a high-carbohydrate load in the diet. This new finding might explain why some patients are successful on a high-carbohydrate low-fat diet, while others prefer to maintain weight with a low-carbohydrate, high-fat diet .
The importance of dietary adherence is of great concern for the success of any diet study. The study conducted by Shai et al.  that was able to control for the feeding of at least one meal a day (cafeteria meal), might better reveal the true effects of a sustained ketogenic diet. The Shai study  compared a low-fat, restricted-calorie diet (LFD), a Mediterranean, restricted-calorie diet (MD), and a low-carbohydrate, non-restricted calorie diet (LC) on 322 moderately obese subjects over a period of two years. The dietary adherence was >85% at the end of two years. This study instructed the LC group to be ketogenic for the first 2 months (<20 g/day) and gradually increase to 120 g/day of carbohydrates. The results found that the greatest weight loss occurred in the low-carb group and both the LC and MD were more effective than the LFD. Although, the weight loss during the first 3 months in the LC group was significantly greater than either of the other two groups, as carbohydrates were added back into their diet, their weight rebounded back to a level close to the MD group. Shai et al.  found that one of the benefits of the LC group was the similar calorie deficit achieved even though it was not a calorie-restricted diet. The researchers propose that a LC diet may be the optimal choice for individuals that cannot follow a calorie restricted diet since these subjects will be permitted to eat until satiated but will still most likely end up lowering their total caloric intake.
A similar long-term (56 week) ketogenic study was conducted on 66 obese people with a BMI >30 . All patients were instructed to eat <20 g of carbohydrates in the form of green vegetables and salads for 12 weeks and then they could increase the carbohydrates to 40 g/day for the remainder of the study. The weight and body mass index of all patients decreased significantly. More interestingly, the patients were advised to maintain a state of nutritional ketosis and they were able to show continued decreases in both BW and BMI throughout the study. Consequently, this study did not show the plateau and gradual increases seen in the Shai study  which allowed the reintroduction of carbohydrates after the initial weight loss period. A similar study by Samaha et al.  also found that patients lost significantly more weight on a 30 g/carbohydrate per day diet for six months compared to a LFD. Another possible benefit from the ketogenic diet is that there is a measurable biomarker that signifies dietary adherence, which is β-hydroxybutyrate (BHB). When an individual is in ketosis, the body will begin ketone production and the level of BHB in the blood will be over 0.5 mmol. Studies that include this measurement can therefore confirm dietary adherence and determine the true effects of the diet on health outcomes, like weight loss. Mohorko et al.  conducted a 12-week ketogenic diet study on obese patients who were calorie restricted (1200–1500 kcal) for the first two weeks and then were instructed to eat ad-libitum for hunger for the remaining weeks while eating the macronutrient composition necessary to remain in a state of nutritional ketosis. BHB was measured throughout the study and patients maintained levels above 0.5 mmol throughout the 12 weeks. Patients showed significant weight loss in both the men and women groups (average of (-)18 kg for men and (-)11 kg for women). Interestingly, as the diet progressed, the patients Fat Mass (FM) became the largest component of weight loss and it significantly correlated with BHB. Another valuable outcome in this study was the reduction of the hunger hormone, leptin, as well as a slight increase in energy expenditure, even while weight decreased throughout all 12 weeks. Another long-term study was done by Hallberg et al.  which followed diabetic patients on a ketogenic diet for one year. At the beginning of this study, 92% of the patients in the ketogenic group were obese. These patients were instructed to eat less than 30 g of total carbohydrates per day and the goal was to maintain BHB blood levels of 0.5–3.0 mmol/L. These patients had an average of 12% decrease in body weight, with some patients achieving as high as ~40% change. The patients who were in the standard care diet group (American Diabetic Association recommended diet) did not see any significant change in body weight .
A short-term, 4-week ketogenic diet (KD) on 20 obese Chinese females had profound outcomes . In this study, compliance to the diet was measured with urinary ketone strips. These participants were given a monitored 4-week normal diet which was followed up with a 4-week KD with the same daily caloric intake but a drastic reduction in carbohydrates to <10% of calories. The effect was a significant decrease in body weight, body mass index, waist circumference, hip circumference, body fat %, and decreased fasting leptin levels. Similar positive outcomes were seen in other KD diet studies [56,63,64]. Similarly, a recent meta-analysis concluded that very low-calorie ketogenic diets are a very effective strategy for treating obesity . An 8-week study conducted by Goss et al.  compared the very low carbohydrate diet (VLCD) (<10% carbohydrates) to a low-fat diet in older obese adults with BMI between 30 and 40. This study precisely measured fat loss with DXA and MRI measurements. Both groups exhibited decrease in total fat, but the VLCD experienced ~3 fold greater decrease in visceral adipose tissue and a significant decrease in intermuscular adipose tissue with a 5-fold greater reduction in total body fat mass.
Another long-term study monitored weight loss as well as changes in visceral fat mass using DEXA. The study by Moreno et al.  compared a very low-calorie ketogenic diet (VLCK) to a low-calorie (LC) diet as a treatment for obesity over two years. Participants in the active stage consumed 600–800 kcal/day and <50 g of carbohydrates per day until they were 80% of target weight loss goals (stage 1). Urinary ketone strips were used during stage 1 to confirm a state of ketosis. Then they used a standard low-calorie diet (10% below total metabolic expenditure) during stage 2 until they achieved another 20% weight loss, followed by long-term maintenance of weight loss in stage 3. The comparison control group used the low-calorie diet throughout the study to achieve weight loss. The weight loss in kilograms in the VLCK diet was double that of the LC diet throughout most of the study and remained significant. The amount of visceral fat loss in the VLCK diet group was 3X greater than the control group while preserving lean body and skeletal bone mass. The main side effects recorded in the VLCK were fatigue, headache, constipation, and nausea. However, none of these side effects were severe enough to cause the patients to drop out of the study and most subsided within the first month .
A meta-analysis conducted by Bueno et al.  compared randomized controlled trials of very low carb ketogenic diets (VLCKD) with low fat diets for 1 year. This study found a significant difference in decreased body weight for the VLCKD group. Another study compared a KD (<30 g carbohydrates/day) with two control groups (standard American diet (SAD) without exercise and SAD with 3-5 days of exercise for 30 minutes) over ten weeks . The KD outperformed the other control groups in all variables tested, with 5 out of 7 being statistically significant. The patients showed significant decreases in body mass index (BMI), body fat mass (BFM), and weight while their resting metabolic rate (RMR) increased. The RMR in the experimental group produced a positive, sizeable change with a magnitude of slope that was more than 10X the two control SAD groups. These results reveal that diet plays a more significant role in outcomes than exercise .
The ability to control hunger is also a key component to weight loss success. Castro et al.  evaluated patients from the very low-calorie ketogenic diet (VLCK) study and found a negative correlation between BHB levels and the urge to eat and feelings of hunger during the phase of maximum ketosis, even though there was no significant change in ghrelin hormone. This result is supported by other large investigations in overweight and obese adults which also found that low-carbohydrate diets were more effective in controlling hunger than low-fat diets [71,72]. A 2-week study conducted by Choi et al.  compared varying nutrition drinks on weight loss in obese adults. There were three groups: 4:1 fat to protein and carbohydrate ratio, 1.7:1 ratio with increased protein, and a balanced nutrition drink with similar carbohydrates to recommended dietary advice. All groups decreased body weight and body fat mass, but only the 1.7:1 KD-group maintained protein mass. Furthermore, only the KD groups improved blood lipid levels with appetite reduction. Since this was a nutritional drink feeding study, all the groups had similar caloric reduction; thus, results were due to macronutrient composition. In addition, levels of ketosis were strongly related to positive differences in food cravings, alcohol cravings, physical activity, sleep patterns, and sexual activity . This outcome might also be supported by a recent finding that postprandial glycemic dips were the best predictor of appetite and energy intake following a meal and large glycemic dips are usually associated with high carbohydrate consumption . Furthermore, a study showed that high carbohydrate meals had a greater impact on brain reward and homeostatic activity in ways that could impede weight loss maintenance . Interestingly, the increased brain activity findings were partially associated with higher insulin levels, too. Thus, the ability of the KD to reduce hunger, lower glycemic fluctuations, and reduce influences on areas of the brain associated with addiction are all positive signs that a ketogenic diet should be considered as a treatment option for obesity.
One of the major concerns for rapid weight loss is the lowering of the resting metabolic rate (RMR). This bodily change can lead to weight regain, which is known as adaptive thermogenesis. Thus, it is typical for hunger to increase and energy expenditure to decrease during weight loss, which is a hindrance to long-term weight loss maintenance. Gomez-Arbelaez et al.  tested this outcome in subjects on the very low-calorie ketogenic (VLCK) diet study and followed them for 2 years. In this study, twenty obese patients lost 20.2 kg of body weight after four months and sustained this weight loss without the expected reduction in RMR. Authors of the study hypothesize that RMR did not drop because the subjects maintained their lean body mass. DEXA scans revealed that although they lost ~20 kg of fat mass, they only lost 1 kg of muscle mass. This conclusion was also supported by normal renal activity and positive nitrogen balance while subjects maintained their fat loss upon follow-up .
A study by Hall et al.  hypothesized that the development of obesity is “a consequence of the insulin-driven shift in fat partitioning toward storage and away from oxidation resulting from an increased proportion of dietary carbohydrates.” To test this hypothesis, they tested seventeen obese men in metabolic wards with a four-week high-carbohydrate diet followed by a four week, isocaloric ketogenic diet. The results showed that a state of ketosis increased energy expenditure (~100 kcal/d), most likely due to beta oxidation and the partitioning of fuel towards ATP production rather than fat storage . However, this level of energy expenditure change due to a ketogenic diet is not as high as measured in another study. In the study by Ebbeling et al. , it was noted that short-term feeding studies do not consider the body’s process of fat adaptation, which takes at least 2–3 weeks, if not longer. Thus, the Framingham study by Ebbeling et al.  conducted a randomized trial on 164 patients where they lost weight and were then placed on varying diets of carbohydrate content for twenty weeks to measure changes in energy expenditure. The difference in total energy expenditure was 209–278 kcal/d or around 60 kcal/d increase for every 10% decrease in the carbohydrate percentage of total energy intake. This study concluded that dietary quality could affect energy expenditure independently of body weight. In accordance, Mobbs et al.  has suggested that ketogenic diets “reverse obesity by preventing the inhibitory effects of lipids on glycolysis, thus maintaining relatively elevated post-prandial thermogenesis.” Further studies will need to be conducted to evaluate and confirm the exact mechanisms of action.
More recent studies on the KD are analyzing the outcomes of the diet in conjunction with other comorbidities related to obesity. A small study was conducted by Carmen et al.  that followed three obese participants on a 10% carbohydrate KD for 6–7 months that exhibitied comorbid binge eating and food addiction symptoms. No adverse effects were found, and participants had reductions in binge eating episodes and food addiction symptoms. All three lost 10–24% BW and maintained treatment outcomes 9–17 months after initiating the diet and continued adherence to the diet . Another study looked at the outcomes for male and female severely obese patients who also suffered from non-alcoholic fatty liver syndrome (NAFLD) . They used a very low-calorie ketogenic diet of <50 g of carbohydrates and <800 kcal/day. Both males and females showed significant losses in body weight. However, males lost significantly more weight and had greater reductions in waist circumference. The patients also improved their biomarker for NAFLD, which was a reduction in gamma-glutamyl transferase . To determine if the ketogenic diet negatively affects kidney function, Bruci et al.  conducted a 3-month very low-calorie ketogenic diet (VLCKD) study for weight loss in obese patients with and without mild kidney failure. All patients were advised to consume <20 g carbohydrates and 500–800 calories per day. The average mean weight loss from initial weight was nearly 20%, participants had significant reduction in fat mass, and 27.7% of the patients with mild kidney failure acquired normalized glomerular filtrate rate. It was, therefore, concluded that a KD not only leads to weight loss but also improvement in kidney function.
Please refer to Table S1 in the Supplementary Materials for a comparison of studies evaluating the KD in relation to weight loss outcomes.