Ghrelin is a peptide hormone secreted primarily by endocrine cells found in the stomach. When ghrelin is released, it acts on receptors in the hypothalamus to stimulate food intake and weight gain. Because of its effects on food intake and weight gain, ghrelin has received considerable attention as a possible target in the treatment of conditions like anorexia nervosa (AN), where stimulation of food intake or weight gain is desired.
In individuals with anorexia nervosa, previous studies have indicated that intravenous administration of ghrelin was associated with increased food intake; however, it is not known whether levels of ghrelin play a role in long-term weight homeostasis in individuals with AN. A recent study from Youngjung Rachel Kim, MD, PhD from the Center for Quantitative Health at Mass General and colleagues in the Eating Disorders Clinical and Research Program, in collaboration with the Neuroendocrine Unit at Mass General, has examined whether endogenous ghrelin levels are associated with longitudinal weight gain trajectories in individuals with anorexia nervosa and healthy controls.
This prospective cohort study was carried out over 18 months and included 68 girls and women (14 to 21 years of age): 35 with anorexia nervosa and 33 healthy controls of similar Tanner stage (indicating pubertal development). At each visit, fasting blood levels of ghrelin were drawn, and then ghrelin levels were measured after participants ate a 400-kcal meal.
Individuals with AN and healthy controls were comparable with regard to race and ethnicity, although those in the AN group were slightly older. In the AN group, BMI percentiles were significantly lower than in the healthy control group at all time points. Across the 18 months of follow-up, weights in the healthy control group remained relatively stable, whereas body weight increased in the AN group over time.
At the baseline visit, circulating ghrelin levels were higher in the AN group than in the healthy controls. In the AN group, higher ghrelin levels at baseline were associated with prospective weight gain after adjusting for diagnosis, age, race, and duration of follow-up. In healthy controls, however, ghrelin levels were not associated with longitudinal weight gain.
New Targets for the Treatment of Anorexia Nervosa
This prospective cohort study found that endogenous levels of ghrelin at baseline were positively associated with longitudinal weight gain in girls and young women with AN over 18 months of follow-up. However, this association between ghrelin levels and weight gain was not observed in healthy controls. Although ghrelin has short-term appetite-stimulating effects, the current report and previous studies in healthy adults have not observed a correlation between endogenous ghrelin levels and longitudinal weight gain.
Prior studies have documented higher levels of ghrelin in underweight individuals with anorexia nervosa; this represents an adaptive response to undernutrition with the goal of increasing food intake and promoting weight gain. The current study is the first to document an association between higher ghrelin levels and longitudinal weight gain in adolescents and young adults. A similar association between ghrelin levels and prospective weight gain has only been observed in infants born small for gestational age. The authors thus speculate that while ghrelin may not play a central role in promoting weight gain in most healthy individuals, ghrelin may occupy a more central role in stimulating food intake in situations where body weight is lower than expected for a specific developmental stage.
The findings of the current study indicate that modulating the ghrelin pathway may help to promote weight restoration in underweight individuals with anorexia nervosa. For instance, a small randomized clinical trial evaluated the effects of a ghrelin receptor agonist, relamorelin, administered subcutaneously, on weight gain in women with AN. In this preliminary study, treatment with the ghrelin agonist was associated with greater weight gain compared to placebo. Larger studies in more diverse populations of individuals with AN are needed to better understand the role of ghrelin in weight homeostasis. Understanding the association between ghrelin levels and longitudinal weight gain is critical as there is an urgent need for novel therapies to assist with weight restoration in this population.
Other contributors to this study include Meghan Lauze, Meghan Slattery, Roy Perlis, Laura Holsen, Lauren Breithaupt, Casey Stern, Maurizio Fava, Jennifer Thomas, Elizabeth Lawson, Madhusmita Misra, and Kamryn Eddy.
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Kim YR, Lauze MS, Slattery M, Perlis RH, Holsen LM, Breithaupt L, Stern CM, Fava M, Thomas JJ, Lawson EA, Misra M, Eddy KT. Association Between Ghrelin and Body Weight Trajectory in Individuals With Anorexia Nervosa. JAMA Netw Open. 2023 Mar 1; 6(3):e234625.
Youngjung Rachel Kim, MD, PhD, is a psychiatrist in the Center for Quantitative Health at Massachusetts General Hospital and an instructor in Psychiatry at Harvard Medical School. As a physician-scientist with clinical expertise in caring for patients with eating disorders, Dr. Kim’s research focuses on improving clinical outcomes in anorexia nervosa, including developing new therapies by leveraging molecular research using patient-derived cellular models in parallel with longitudinal clinical studies.
