Highlightsd 20 inpatient adults received ultra-processed and unprocessed diets for 14 days each d Diets were matched for presented calories, sugar, fat, fiber, and macronutrients d Ad libitum intake was 500 kcal/day more on the ultraprocessed versus unprocessed diet d Body weight changes were highly correlated with diet differences in energy intake

Objective To measure long-term changes in resting metabolic rate (RMR) and body composition in participants of The Biggest Loser competition. Methods Body composition was measured by dual energy X-ray absorptiometry and RMR was determined by indirect calorimetry at baseline, at the end of the 30 week competition, and 6 years later. Metabolic adaptation was defined as the residual RMR after adjusting for changes in body composition and age. Results Of the 16 Biggest Loser competitors originally investigated, 14 participated in this follow-up study. Weight loss at the end of the competition was (mean±SD) 58.3±24.9 kg (p<0.0001) and RMR decreased by 610±483 kcal/d (p=0.0004). After 6 years, 41.0±31.3 kg of the lost weight was regained (p=0.0002) while RMR was 704±427 kcal/d below baseline (p<0.0001) and metabolic adaptation was −499±207 kcal/d (p<0.0001). Weight regain was not significantly correlated with metabolic adaptation at the competition’s end (r=−0.1, p=0.75) but those subjects maintaining greater weight loss at 6 years also experienced greater concurrent metabolic slowing (r=0.59, p=0.025). Conclusions Metabolic adaptation persists over time and is likely a proportional, but incomplete, response to contemporaneous efforts to reduce body weight.

BACKGROUND. Mirabegron is a β3-adrenergic receptor (β3-AR) agonist approved only for the treatment of overactive bladder. Encouraging preclinical results suggest that β3-AR agonists could also improve obesity-related metabolic disease by increasing brown adipose tissue (BAT) thermogenesis, white adipose tissue (WAT) lipolysis, and insulin sensitivity. METHODS. We treated 14 healthy women of diverse ethnicities (27.5 ± 1.1 years of age, BMI of 25.4 ± 1.2 kg/m 2) with 100 mg mirabegron (Myrbetriq extended-release tablet, Astellas Pharma) for 4 weeks in an open-label study. The primary endpoint was the change in BAT metabolic activity as measured by [ 18 F]-2-fluoro-d-2-deoxy-d-glucose (18 F-FDG) PET/CT. Secondary endpoints included resting energy expenditure (REE), plasma metabolites, and glucose and insulin metabolism as assessed by a frequently sampled intravenous glucose tolerance test. RESULTS. Chronic mirabegron therapy increased BAT metabolic activity. Whole-body REE was higher, without changes in body weight or composition. Additionally, there were elevations in plasma levels of the beneficial lipoprotein biomarkers HDL and ApoA1, as well as total bile acids. Adiponectin, a WAT-derived hormone that has antidiabetic and antiinflammatory capabilities, increased with acute treatment and was 35% higher upon completion of the study. Finally, an intravenous glucose tolerance test revealed higher insulin sensitivity, glucose effectiveness, and insulin secretion. CONCLUSION. These findings indicate that human BAT metabolic activity can be increased after chronic pharmacological stimulation with mirabegron and support the investigation of β3-AR agonists as a treatment for metabolic disease. TRIAL REGISTRATION. Clinicaltrials.gov NCT03049462.

Summary Dietary carbohydrate restriction has been purported to cause endocrine adaptations that promote body fat loss more than dietary fat restriction. We selectively restricted dietary carbohydrate versus fat for 6 days following a 5 day baseline diet in 19 adults with obesity confined to a metabolic ward where they exercised daily. Subjects received both isocaloric diets in random order during each of two inpatient stays. Body fat loss was calculated as the difference between daily fat intake and net fat oxidation measured while residing in a metabolic chamber. Whereas carbohydrate restriction led to sustained increases in fat oxidation and loss of 53±6 g/d of body fat, fat oxidation was unchanged by fat restriction leading to 89±6 g/d of fat loss and was significantly greater than carbohydrate restriction (p=0.002). Mathematical model simulations agreed with these data, but predicted that the body acts to minimize body fat differences with isocaloric diets varying in carbohydrate and fat.