ClinicalTrials.gov NCT01778556FUNDING. This research was supported by the intramural research program of the NIDDK.

Key Points Question Which factors are associated with county-level variation in obesity prevalence, and how can they be identified using epidemiologic and machine learning methods? Findings This cross-sectional study of 3138 US counties found significant county-level variation in obesity prevalence, with US Census region, median household income, and percentage of population with some college education being most strongly associated with obesity prevalence. Machine learning models explain two-thirds more variation in obesity but were less interpretable than multivariate linear regression models. Meaning Machine learning models of county-level demographic, socioeconomic, health care, and environmental factors explain significantly more variation in obesity prevalence while being less interpretable.

Context Leptin is an adipokine that signals energy sufficiency. In rodents, leptin deficiency decreases energy expenditure (EE), which is corrected following leptin replacement. In humans, data are mixed regarding leptin-mediated effects on EE. Objective To determine the effects of metreleptin on EE in patients with lipodystrophy. Design, setting, and patients Non-randomized crossover study of 25 patients with lipodystrophy (NIH, 2013-2018). Intervention The initiation cohort consisted of 17 patients without prior exposure to metreleptin, studied before and after 14 days of metreleptin. The withdrawal cohort consisted of 8 previously metreleptin-treated patients, studied before and after 14 days of metreleptin withdrawal. Main outcomes 24-hour energy expenditure (TEE), resting energy expenditure (REE), autonomic nervous system activity (heart rate variability, HrV), plasma free T3, free T4, epinephrine, norepinephrine, and dopamine. Results In the initiation cohort, TEE and REE decreased by 5.0% (121±152 kcal/day; p=0.006) and 5.9% (120±175 kcal/day; p=0.02). Free T3 increased by 19.4% (40±49 pg/dL; p=0.01). No changes in catecholamines or HrV were observed. In the withdrawal cohort, free T3 decreased by 8.0% (p=0.04), free T4 decreased by 11.9% (p=0.002), and norepinephrine decreased by 34.2% (p=0.03), but no changes in EE, epinephrine, dopamine, or HrV were observed. Conclusions Metreleptin initiation decreased EE in patients with lipodystrophy, but no changes were observed after metreleptin withdrawal. Thyroid hormone was higher on metreleptin in both initiation and withdrawal cohorts. Decreased EE after metreleptin in lipodystrophy may result from reductions in energy-requiring metabolic processes that counteract increases in EE via adipose tissue-specific neuroendocrine and adrenergic signaling.

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