Obeying the Law: Energy Balance in Alternate-Day Fasting, Exercise, or Both Together in Patients With Obesity and NAFLD

Ezpeleta M, Gabel K, Cienfuegos S, et al. Effect of alternate day fasting combined with aerobic exercise on nonalcoholic fatty liver disease: a randomized controlled trial. Cell Metab 2023;35:56–70.e3. The First Law of Thermodynamics states that energy can neither be created nor destroyed, only altered in form. Simply put, energy balance in obesity comprises input and expended energy. Lifestyle interventions for patients with obesity, insulin resistance, and nonalcoholic fatty liver disease (NAFLD) often address both aspects of energy input (“diet”) and energy expenditure (“exercise”). Perhaps out of expediency, “diet and exercise” are recommended as if this represents a single intervention. Yet, either intervention by itself often represents a major personal upheaval. As a result, adherence to either intervention alone, let alone in combination, can be difficult and short-lived. This raises a few clinically important questions. Could we achieve desired metabolic effects by inaugurating a single intervention, and if so, which one? What is the adherence and durability of the intervention? Ezpeleta et al recently compared the efficacy of short-term interventions on several metabolic parameters in adults with obesity and NAFLD (defined as magnetic resonance proton density fat fraction >5%). They randomized 80 patients to explore the effect of alternate-day fasting (ADF) alone (600 kcal/d alternating with ad libitum feeding), exercise alone (5 days/wk, 60-minute supervised aerobic activity session at 60%–85% maximum heart rate), a combination of the two, or no intervention. Overall, 3-month combination therapy induced improvements in multiple metabolic parameters (intrahepatic triglycerides, body weight, fat mass, waist circumference, and several markers of insulin resistance) vs control and exercise-only groups, but it was not more effective at improving any of the measured metabolic outcomes vs ADF alone. Moreover, 85% and 95% of patients in the ADF and combination groups, respectively, desired to continue ADF after the protocol ended, whereas 25% attrition was observed in the exercise-only group, The data give a rare and detailed comparison between intervention groups, with high adherence to intense ADF and supervised routine aerobic exercise over a brief interval. Limitations include small sample sizes (n = 20 per group), and a larger sample size may better resolve the efficacy of these interventions. The data, however, are informative regarding attrition in the exercise-only group, 25%, even in a motivated and closely observed population. Thus, although ADF monotherapy compared more favorably overall vs diet and exercise, and although adherence was high in this intervention, one might not yet conclude unequivocally that ADF monotherapy is to be recommended where combination therapy is unattainable. Nevertheless, the data do demonstrate that time-limited intensive combination diet and exercise intervention improves multiple body morphometry and liver fat better than exercise, but not better than ADF alone on the same measures. And although each patient’s individual intervention is always tailored to their disposition, tolerance, and clinical needs, these data are some of the first to allow more fully informed clinical decisions to treat obesity, NAFLD, and their complications by intervening on energy balance. The data will certainly be informative, at least for now, while we remain beholden to the laws of thermodynamics.