Scientists have revealed deep insights into the role that a little-understood human hormone plays in regulating body weight. Named Growth and Differentiation Factor 15 (GDF15), this hormone is typically active only when the body experiences acute or prolonged stress, including following exposure to tissue-damaging toxins, such as chemotherapy, or during chronic disease, such as obesity or cancer. As a result, the GDF15 pathway holds promise for the development of potential therapeutics for diseases of both excess and insufficient body weight.
The paper, published in Nature, uncovers important molecular biology and mechanisms related to this hormone and its receptor, including the crystal structure of the complex. Based on these preclinical findings, researchers are advancing multiple drug candidates, including NGM386. NGM386 is an optimized variant of GDF15 that activates its cognate receptor, known as GDNF Receptor Alpha-like (GFRAL), and holds potential as a treatment for obesity, a growing epidemic that affects an estimated 78 million adults in the United States. They are also developing NGM120, a monoclonal antibody antagonist of GFRAL that holds potential as a treatment for cachexia. Cachexia is an extreme form of weight loss exacerbated by chemotherapy that afflicts more than half of all cancer patients, for whom it is frequently the proximate cause of death.
The paper shows that GDF15 binding to GFRAL is required both to protect mice from weight gain in metabolically-stressed conditions and to trigger excessive weight loss in mice treated with chemotherapy. This work also demonstrated that GFRAL forms a complex with the receptor tyrosine kinase RET on the surface of neurons that are localized exclusively in the brainstem, and that these neurons form part of what has been recently dubbed the "emergency circuit" of body weight regulation. This circuit, which resides deep within the brain, lies outside of those areas normally associated with weight control. Until recently, the identity of circulating molecules that could activate this circuit remained elusive. By binding to GFRAL and activating RET, GDF15 'flips the switch' on this circuit, leading to anorexia and weight loss.
Authors show that Gfral knockout mice are hyperphagic under stressed conditions and are resistant to chemotherapy-induced anorexia and body weight loss. GDF15 activates GFRAL-expressing neurons localized exclusively in the area postrema and nucleus tractus solitarius of the mouse brainstem. It then triggers the activation of neurons localized within the parabrachial nucleus and central amygdala, which constitute part of the ‘emergency circuit’ that shapes feeding responses to stressful conditions.
GDF15 levels increase in response to tissue stress and injury, and elevated levels are associated with body weight loss in numerous chronic human diseases. By isolating GFRAL as the receptor for GDF15-induced anorexia and weight loss, authors identify a mechanistic basis for the non-homeostatic regulation of neural circuitry by a peripheral signal associated with tissue damage and stress.