We previously reported superior responses with a VLCK over a LF diet in a number of cardiovascular risk factors in these subjects [25, 27]. The results of this study demonstrate that short-term VLCK diets also outperform LF diets in terms of weight loss and fat loss. These effects occurred despite apparently similar energy deficits between diets and in the case of men, significantly greater energy intake. Greater weight loss with a VLCK over a LF diet is consistent with the findings from other studies, and provides further support for the concept of metabolic advantage [7, 8]. Since food was not provided this conclusion cannot be made with certainty, but we find it highly unlikely that any potential error in quantifying energy intake would account for the dramatic differences in weight and fat loss between diets. We can say with confidence that we studied subjects that were restricting carbohydrates to very low levels as verified by dietary food records, urine ketones, and low resting respiratory exchange ratios obtained with indirect calorimetry.
The basic principle on which weight loss diets are based is to reduce dietary energy intake below energy expenditure. Whether the relative composition of macronutrients can influence the magnitude or composition of weight loss achieved on an energy-restricted diet has been a point of contention. Several comparisons of isocaloric VLCK and LF diets, like the current report, show greater weight loss on a VLCK diet [6, 16] supporting the long held notion of a metabolic advantage . Given such evidence, it is difficult to understand the alternate position claiming a calorie must be a calorie in order to satisfy the first law of thermodynamics . Although the origin of the difference in weight loss between VLCK and LF diets remains controversial, such a response clearly does not violate any thermodynamic laws . Not all studies have shown greater weight loss with a VLCK diet  and the specific conditions that are required to elicit a metabolic advantage remain unknown.
One argument is that the greater weight loss on ad libitum VLCK diets is a result of spontaneously reducing energy intake , and this has been reported previously . A reduction in energy intake on a VLCK diet has a logical physiologic basis and could account for a portion of the greater weight observed in studies that involved free-living ab libitum VLCK diets. Ketone levels increase several-fold on a VLCK diet, and β-hydroxybutyrate (the major circulating ketone body) has been shown to directly inhibit appetite . Also, the low glycemic nature of a VLCKD may prevent transient dips in blood glucose, which can occur with higher carbohydrate diets. Thus, avoidance of hypoglycemic episodes may reduce appetite . In this study we did not report a significantly lower energy intake on the VLCK compared to the LF diet. In fact, a higher energy intake was observed on the VLCK diet in men. In this case, it is often claimed that inaccurate reporting of dietary intake or errors in nutrient databases (e.g., overestimation of calories from certain cuts of meats) account for the greater weight reducing effects of VLCK diets. On the other hand, LF diets are frequently encouraged because of their high bulk and over-reporting seems as likely on a LF as a VLCK diet. In the absence of a clear reason why error in these studies should always go in one direction – LF rarely do better than VLCK – one has to take the data at face value. Also, the large difference in weight loss between men on the VLCK and LF diets in the present study suggests that at least some impact of macronutrient composition is being seen.
Metabolic advantage may occur on a VLCK diet due to the demand on protein turnover for gluconeogenesis , greater thermogenic effect of protein and loss of energy as heat [36, 37], and/or excretion of energy in the form of ketones via urine, feces, and/or sweat. Although we did not see a difference in REE, the metabolic advantage on a VLCK diet may be below the sensitivity of our measurements. Further, since REE was obtained in a postabsorptive state, this does not rule out a potential benefit derived from the acute postprandial thermic effect of protein ingestion. In terms of REE, there was a slight advantage for men on the VLCK diet when expressed relative to body mass, which could benefit long-term weight maintenance but this needs to be validated in studies of longer duration.
Although the issue of whether VLCK diets result in greater weight loss compared to LF diets has obvious significance, a primary purpose of this study and an equally important question relates to the composition of weight loss. In a meta-analysis, Garrow and Summerbell  predict from regression analysis that for a weight loss of 10 kg by dieting alone, the expected loss from fat mass is 71%. The few studies that have assessed body composition suggest that VLCK diets may result in preferential loss of fat mass. Benoit et al.  showed that a 10 day VLCK diet (4.2 MJ/day) resulted in a weight loss of -6.6 kg in obese men, 97% of which was fat mass. Young et al.  compared the effects of three isoenergetic (7.5 MJ/day), isoprotein (115 g/day) diets containing varying carbohydrate contents (30, 60, and 104 g/day) on weight loss and body composition in obese men. After 9 weeks, weight loss was 16.2, 12.8, and 11.9 kg and fat accounted for 95%, 84%, and 75% of the weight lost, respectively. Willi et al.  showed that an 8 week VLCK diet (2.7–3.0 MJ/day) resulted in a weight loss of -15.4 kg and an increase in lean body mass of +1.4 kg in obese adolescents. An 8-week VLCK diet in overweight women resulted in a decrease in body mass of -5 kg, 80% of which was fat mass . Our laboratory recently reported that a 6 week VLCK diet resulted in significant decrease in body mass (-2.2 kg), entirely accounted for by a decrease in fat mass (-3.3 kg) and concomitant increases in lean body mass (+1.1 kg) in normal-weight men . The body composition results from the present study are in closer agreement with predictions from the meta-analysis .
A novel and potentially clinically significant finding was a preferential loss of fat in the trunk region with a VLCK diet, which was approximately three-fold greater during the VLCK than the LF diet. Upper body fat carries a greater health risk than fat stored in other regions of the body and thus an effective weight loss approach should consider the regional distribution of fat loss. Proportionally, trunk fat mass comprised less of the total fat mass after the VLCK but not the LF diet. The mechanisms regulating composition of weight loss and distribution of fat loss during VLCK diets remain unclear, but could be mediated in part by changes in hormones such as insulin, leptin, or cortisol that could differentially impact nutrient partitioning.
In summary, this study showed greater weight loss and fat loss preferentially from the trunk region in subjects on a closely monitored free-living VLCK diet compared to a LF diet. These diets were prescribed to be energy restricted and isocaloric. The superiority of the VLCK diet over the LF diet was most dramatic for men, but when individual responses were examined, a group of women clearly showed metabolic advantage as well. Indeed, 12/13 women experienced greater fat loss in the trunk region during the VLCK diet compared to the low-fat diet. Such a response is consistent with a metabolic advantage of VLCK diets. The ultimate proof for such a theory will depend on the findings from carefully controlled feeding and metabolic studies that encompass physiological measurements to isolate plausible mechanisms.