ESPE Yearbook of Paediatric Endocrinology

To read the full abstract: Nature Communications, 2019; 10 (1); 662

This paper highlights the brain as a key target for growth hormone (GH) signaling affecting mostly energy conservation. To identify GH response neurons, C57BL/6 mice received intraperitoneal injection of saline or GH and their brains were processed to detect the phosphorylation of pSTAT5 as a marker of GH receptor activation. They found that GH acts directly on brain GH receptors to conserve energy when the body loses weight. It influences the metabolic responses that conserve energy when we are hungry or on a diet with important implications in terms of understanding why it is so hard to lose weight.

Leptin has until now been considered the main hormone that acts to conserve energy when we are hungry. GH acts on the brain in a similar way to leptin. Only that leptin levels fall, and GH levels rise in response to weight loss, while GH receptors, GH-binding proteins and circulating IGF1 levels decrease. Brain GH receptors are located in the hypothalamus. Signals from the hypothalamus influence the cells of the autonomic nervous system and activate Agouti Related Protein (AgRP), which acts to increase appetite and to diminish energy metabolism and expenditure.

Here, the authors studied genetically modified mice with AgRP-specific GH receptor ablation (KO). When subjected to a diet with 60% food restriction, energy expenditure decreased in control mice, but significantly less so in AgRP GHR KO mice, suggesting that they did not save energy as efficiently, and so displayed a higher rate of weight loss, primarily greater loss of fat mass (energy reserves) but also loss of lean mass and the mass of vital organs, i.e. bone, muscle, ligaments, tendons, and body fluids.

So, evolution has endowed humans with two energy conserving mechanisms: one activates by decreasing peripheral leptin; the other by increasing pituitary GH. These findings help to explain why leptin replacement does not completely reverse the neuroendocrine adaptations induced by weight loss, since both GH and leptin play a role informing the brain about energy deficiency. Thus, pharmacological compounds that block GH signaling may prevent the compensatory decrease in energy expenditure during dieting and consequently represent a promising approach to facilitate weight loss.