ESPE Yearbook of Paediatric Endocrinology

To read the full abstract: Proc Natl Acad Sci U S A 2019;116(27):13670–13679. doi: https://pubmed.ncbi.nlm.nih.gov/31213533/

In this paper, Perry et al. studied several animal models to disentangle the mechanism by which leptin suppresses hunger. In rats, the hyperphagia induced by a 48 h fast, or a hypoglycemic hyperinsulinemic clamp, or uncontrolled diabetes, was completely suppressed by treatment with a glucocorticoid receptor antagonist, despite low leptin levels. In contrast, external administration of corticosterone overcame the food suppressive effects of leptin rescue. In mice, overexpression of the cortisol inactivating enzyme 11β-hydroxysteroid dehydrogenase type 2 in agouti-related peptide producing neurons suppressed both fasting and corticosterone-induced hyperphagia. Both fasting and corticosterone administration increased firing rate in electrophysiological studies.

From their results, the authors conclude that hyperphagia in fasting and poorly controlled diabetes is dependent upon hypercorticosteronemia, and leptin’s effect on food intake is mediated via suppression of the hypothalamus-adrenocortical axis.

With these observations, the authors add an important piece of information to the complex regulation of satiety in very thorough experiments, thus returning to the old model that glucocorticoids are at the centre of energy balance. However, they are not the first group to examine this interaction, and previous results are contradictory. While one group also found that leptin administration can suppress raised corticosterone levels in rats with uncontrolled diabetes (1), in contrast others observed an increase in corticosterone production by leptin treatment in rats both in vivo (2) and also in vitro (3). Also, in a previous study in adrenalectomized ob/ob mice, leptin reduced food intake and body weight independently of absence or presence of concomitant corticosterone substitution (4). This complexity is highlighted by the fact that even in the current study, the reduction of elevated corticosterone levels in fasted rats by leptin substitution did not reach significance.

Therefore, the conclusion of these authors is maybe too bold – suppression of an activated hypothalamus-adrenocortical axis might be one pathway through which leptin suppresses hunger in rodents, but most likely not the only one.

How much of a role this mechanism of leptin action plays in humans remains even less clear. While one study in humans with congenital leptin deficiency (CLD) found increased cortisol levels in the leptin-naïve state (5), no other study replicated this finding (6, 7). Furthermore, leptin substitution in CLD patients did not reduce cortisol levels (6) but even increased them (8).

References:

1. German JP, Wisse BE, Thaler JP, Oh IS, Sarruf DA, Ogimoto K, et al. Leptin deficiency causes insulin resistance induced by uncontrolled diabetes. Diabetes. 2010;59 (7):1626–34.

2. Malendowicz LK, Macchi C, Nussdorfer GG, Nowak KW. Acute effects of recombinant murine leptin on rat pituitary-adrenocortical function. Endocrine Research. 1998;24 (2):235–46.

3. Malendowicz LK, Nussdorfer GG, Markowska A. Effects of recombinant murine leptin on steroid secretion of dispersed rat adrenocortical cells.The Journal of steroid biochemistry and molecular biology. 1997;63 (1–3):123–5.

4. Arvaniti K, Ricquier D, Champigny O, Richard D. Leptin and corticosterone have opposite effects on food intake and the expression of UCP1 mRNA in brown adipose tissue of lep(ob)/lep(ob) mice. Endocrinology 1998;139 (9):4000–3.

5. Ozata M, Ozdemir IC, Licinio J. Human leptin deficiency caused by a missense mutation: multiple endocrine defects, decreased sympathetic tone, and immune system dysfunction indicate new targets for leptin action, greater central than peripheral resistance to the effects of leptin, and spontaneous correction of leptin-mediated defects. J Clin Endocrinol Metab. 1999;84 (10):3686–95.

6. Farooqi IS, Matarese G, Lord GM, Keogh JM, Lawrence E, Agwu C, et al. Beneficial effects of leptin on obesity, T cell hyporesponsiveness, and neuroendocrine/metabolic dysfunction of human congenital leptin deficiency. The Journal of clinical investigation. 2002;110 (8):1093–103.

7. Fischer-Posovszky P, von Schnurbein J, Moepps B, Lahr G, Strauss G, Barth TF, et al. A new missense mutation in the leptin gene causes mild obesity and hypogonadism without affecting T cell responsiveness. J Clin Endocrinol Metab. 2010;95 (6):2836–40.

8. Licinio J, Caglayan S, Ozata M, Yildiz BO, de Miranda PB, O’Kirwan F, et al. Phenotypic effects of leptin replacement on morbid obesity, diabetes mellitus, hypogonadism, and behavior in leptin-deficient adults. Proc Natl Acad Sci USA. 2004;101 (13):4531–6.