The mechanism by which meal ingestion causes thermogenesis remains unknown. Here we show that refeeding leads to a 10x increase in plasma leptin concentrations associated with a 2.5x increase in plasma catecholamine concentrations in 48h-fasted lean rats. This leptin/catecholamine surge was associated with a 1°C increase in body temperature (BT) (fed 35.9±0.1°C, fasted 35.4±0.0°C, P<0.001; refed 36.4±0.1°C, P<0.001 vs. fasted and P<0.05 vs. fed). Leptin infusion in fasted rats replicated these increases in epinephrine and BT. However, the effect of leptin to increase BT was abrogated in adrenalectomized (ADX) rats following refeeding and leptin infusion. Treatment with a β1-adrenergic antagonist (atenolol) or surgical removal of brown adipose tissue (BAT) also prevented leptin- and refeeding-induced thermogenesis. The effect of refeeding to increase leptin and cause thermogenesis depended on the meal composition: a dextrose meal increased leptin, epinephrine, and BT whereas an isocaloric fat meal did not (AUC P<0.01, 0.05, and 0.01, respectively). Meal thermogenesis was not observed in obese rats, in which fasting plasma leptin failed to fall below the threshold (∼1.8 ng/mL) at which reductions in leptin lowered catecholamine concentrations. In order to examine the potential role for meal thermogenesis to regulate energy balance, we compared rats fed for 10 days with a carbohydrate-rich meal replacement by either two boluses daily or a continuous intragastric infusion. Bolus feeding increased BT and reduced BW gain (bolus feeding 0.1±0.3% weight loss vs. continuous feeding 1.7±0.3% weight gain, P<0.001), an effect abrogated by atenolol.

Conclusion: Leptin induces postprandial thermogenesis through stimulation of the hypothalamic-adrenomedullary axis resulting in increased plasma catecholamines, which stimulate BAT through increased β1-adrenergic activity. These results provide a potential mechanism by which time-restricted feeding may improve metabolic health.


R.J. Perry: Research Support; Self; AstraZeneca. A. Rabin-Court: None. J. Dong: None. K. Lyu: None. X. Li: None. G.I. Shulman: Advisory Panel; Self; AstraZeneca, Janssen Research & Development, Merck & Co., Inc. Advisory Panel; Spouse/Partner; Merck & Co., Inc. Board Member; Self; Novo Nordisk A/S. Consultant; Self; Aegerion Pharmaceuticals, IMetabolic BioPharma Corporation, Longitude Capital, Nimbus Discovery, Inc., Staten Biotechnology B.V.


National Institutes of Health (R01DK113984, P30DK059635, T32DK101019, K99/R00CA215315, R01NS087568, UL1TR000142, T32DK007058, R01DK075632, R01DK089044, R01DK096010, R01DK111401)

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