ESPE Yearbook of Paediatric Endocrinology

To read the full abstract: J Clin Invest 2020;130(4):2001–16.

In this study, Perry et al used their well-established animal model of fasted rats to unravel how feeding induces hyperthermia and energy expenditure.

They showed that intracerebroventricular injection of leptin normalized fasting induced low plasma epinephrine and norepinephrine levels and body temperature mimicking postprandial conditions. The rise in body temperature seems to be mediated via β-adrenergic stimulation of adipose tissue triglyceride lipase, mostly in brown adipose tissue (BAT), as antagonism with atenolol fully abrogated the thermogenic responses to both refeeding and to leptin, whereas infusing epinephrine replicated leptin’s effect of raising body temperature. Inhibition of adipose triglyceride lipase abrogated the increase in body temperature observed after epinephrine infusion, which was also reduced by removal of the BAT. The capability of feeding to stimulate leptin production depended on time restriction, as continuous refeeding could not raise leptin, catecholamines levels, or body temperature.

Meal thermogenesis contributes to daily energy expenditure and many (1, 2), although not all (3), studies have shown that meal thermogenesis is diminished in obese individuals, which might contribute to the pathogenesis of obesity. Hence, regulation of food induced thermogenesis is of special interest.

Serum catecholamine concentrations are known to increase after meal ingestion (4), therefore β-adrenergic activity is an interesting potential mediator of postprandial increases in body temperature. Fittingly, it is now well known that in rats intravenous infusion of leptin, (5–7) selective injection of leptin into the brain, (8–11) or site-specific activation of leptin-receptors in the dorsomedial hypothalamus (12) increases sympathetic nervous activity in various tissues including the BAT (6, 8–11).

How readily can we translate these results into humans? So far, it has not been possible to demonstrate an increase in catecholamine levels during leptin substitution in patients with congenital leptin deficiency (13), although leptin might still increase regional sympathetic nervous activity. Of special interest for obese patients is the possibility that feeding stimulates leptin production, catecholamines levels, and body temperature depending on time restriction, which might explain some of the benefits of intermittent fasting (14).

References:

1. Shetty PS, Jung RT, James WP, Barrand MA, Callingham BA. Postprandial thermogenesis in obesity. Clinical science (London, England: 1979). 1981;60 (5):519–25.

2. Blaak EE, Hul G, Verdich C, Stich V, Martinez JA, Petersen M, et al. Impaired fat-induced thermogenesis in obese subjects: the NUGENOB study. Obesity (Silver Spring, Md). 2007;15 (3):653–63.

3. Tentolouris N, Tsigos C, Perea D, Koukou E, Kyriaki D, Kitsou E, et al. Differential effects of high-fat and high-carbohydrate isoenergetic meals on cardiac autonomic nervous system activity in lean and obese women. Metabolism: clinical and experimental. 2003;52 (11):1426–32.

4. Welle S, Lilavivat U, Campbell RG. Thermic effect of feeding in man: increased plasma norepinephrine levels following glucose but not protein or fat consumption. Metabolism: clinical and experimental. 1981;30 (10):953–8.

5. Shek EW, Brands MW, Hall JE. Chronic leptin infusion increases arterial pressure. Hypertension. 1998;31 (1 Pt 2):409–14.

6. Haynes WG, Morgan DA, Walsh SA, Mark AL, Sivitz WI. Receptor-mediated regional sympathetic nerve activation by leptin. The Journal of clinical investigation. 1997;100 (2):270–8.

7. Carlyle M, Jones OB, Kuo JJ, Hall JE. Chronic cardiovascular and renal actions of leptin: role of adrenergic activity. Hypertension. 2002;39 (2 Pt 2):496–501.

8. Dunbar JC, Lu H. Leptin-induced increase in sympathetic nervous and cardiovascular tone is mediated by proopiomelanocortin (POMC) products. Brain Res Bull. 1999;50 (3):215–21.

9. Dunbar JC, Hu Y, Lu H. Intracerebroventricular leptin increases lumbar and renal sympathetic nerve activity and blood pressure in normal rats. Diabetes. 1997;46 (12):2040–3.

10. Rahmouni K, Morgan DA. Hypothalamic arcuate nucleus mediates the sympathetic and arterial pressure responses to leptin. Hypertension. 2007;49 (3):647–52.

11. Mark AL, Agassandian K, Morgan DA, Liu X, Cassell MD, Rahmouni K. Leptin signaling in the nucleus tractus solitarii increases sympathetic nerve activity to the kidney. Hypertension. 2009;53 (2):375–80.

12. Simonds SE, Pryor JT, Ravussin E, Greenway FL, Dileone R, Allen AM, et al. Leptin mediates the increase in blood pressure associated with obesity. Cell. 2014;159 (6):1404–16.

13. von Schnurbein J, Manzoor J, Brandt S, Denzer F, Kohlsdorf K, Fischer-Posovszky P, et al. Leptin Is Not Essential for Obesity-Associated Hypertension. Obesity facts. 2019;12 (4):460–75.

14. Antoni R, Johnston KL, Collins AL, Robertson MD. Effects of intermittent fasting on glucose and lipid metabolism. The Proceedings of the Nutrition Society. 2017;76 (3):361–8.