ESPE Yearbook of Paediatric Endocrinology

Brief summary: Grzelka et al. identified a hypothalamic circuit that regulates regain of body weight after weight loss.

Body weight is one of the most regulated variables of our body, which is most likely due to the evolutionary history of times when access to food was scarce and volatile. Weight loss triggers a strong counterregulatory response. It increases the hunger drive and greatly increases the reward value of food, making it more difficult to adhere to a diet. Furthermore, energy metabolism is slowed down to reduce energy expenditure. Therefore, a weight loss diet is rarely successful in the long term (1). Caloric deprivation results in downregulation of nutrients and hormones, such as leptin, PYY and CCK, which usually suppress hunger, while the appetite-promoting hormone ghrelin becomes upregulated. By acting on orexigenic agouti-related peptide expressing (AgRP) neurons or anorexigenic pro-opio-melanocortin-expressing (POMC) neurons, these peripheral factors are thought to act on the brain to promote diet relapse and weight regain, but the precise mechanism of adaptations to dieting is not understood.

The authors investigated mice after acute overnight fasting causing substantial (>10%) weight loss accompanied by an increased excitatory drive on AgRP neurons. They found that weight loss promotes a connection between AgRP neurons with another upstream neuron population, paraventricular hypothalamic thyrotropin releasing hormone neurons (PVH^TRH) and that activity of this PVH^TRH / AgRP circuit is necessary and sufficient to drive weight (re)gain. Most interesting, activation of this pathway induced persistent weight gain, while blocking the PVH^TRH / AgRP prevented weight gain after fasting.

Although these results need validation in a clinical setting, Gzelka et al. provide evidence of a neuronal pathway consistent with the suggested set-point theory of body weight regulation. Since these experiments were performed in lean mice, it would be interesting to investigate if the identified pathway is also relevant in an obese setting. Furthermore, it would be of particular interest to investigate if this novel pathway interacts with leptin-melanocortin signalling.

Reference: 1. Nordmo M, Danielsen YS, Nordmo M. The challenge of keeping it off, a descriptive systematic review of high-quality, follow-up studies of obesity treatments. Obes Rev 2020; 21. doi: 10.1111/obr.12949.