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Intermittent fasting (IF) approach for weight loss obviates the inconvenience of calorie counting of daily caloric restriction (DCR). It tests IF ability to better counteract a metabolic defense mechanism (MDM) than DCR. MDM obstructs weight loss and facilitates weight regain possibly by increasing hunger and efficiency of exercise energy expenditure (EEf), and by reducing resting metabolic rate (RMR) and physical activity (PA). A knowledge gap exists about whether the duration of weekly uninterrupted fasts (UFs), where the IF protocols are isocaloric, mitigate the MDM. This study compares two IF protocols that have the same weekly number of hours of fast (108) and free access to food (60), but which differ in the duration of UF. An 82-week case report was conducted with twice-weekly near-absolute 36-hour fasts on non-consecutive days (5:2-NC) and compared to ten studies with a 20-hour UF on three non-consecutive days (4:3-NC) modified through provision of a 500-600 kcal meal on fasting days. The large meal raised insulin concentration for 4 hours and reduced the UF to 8 hours followed by 12 nocturnal hours of fasting. The hypotheses were that (1) because of their matched F/E ratio, the rates of weight and fat losses will be similar in both protocols, and (2) because of its longer UF period, hunger will be higher and RMR and voluntary physical activity lower, in 5:8-NC than in M4:3-NC protocol,. The main differences between the two protocols were, (1) slower rates of weight and fat losses, (2) lower sensation of hunger and substantial decline in fullness, no change in RMR and physical activity, and 2.5 times higher post-fast concentration of the ketone body beta-hydroxybutyrate (BHB) in 8:2-NC compared to M4:3-NC protocol. Absence of increased hunger and the variability of the rate of weight loss in 5:2-NC protocol, plus increased EEf in one M4:3-NC study suggest that IF does not curtail MDM, but shortened UF period in M4:3-NC reduces elicitation of BHB. Thus, the addition of a large meal on fasting days is unnecessary for prevention of hunger and is counterproductive for increases in BHB and its potential health benefits.