Endocrine Abstracts

The ability to adapt to changing environmental stimuli, such as the availability of food, is essential for the survival of species. As such, complex mechanisms have evolved to maintain metabolic homeostasis during periods of nutritional challenge. In 2007, the Fibroblast Growth Factor 21 (FGF21) was identified as a nuclear receptor-regulated hepatokine that is induced during starvation. Since then, considerable effort has been devoted to elucidate the breadth of actions of FGF21, its target-tissues, mechanisms of action, and unexpected pharmacological benefits. Consistent with a proposed role in the adaptive starvation response, it was found to induce gluconeogenesis, ketogenesis and insulin sensitivity. It can also promote longevity and food-seeking behaviour, inhibit growth, disrupt the circadian rhythm, and cause female infertility. We showed that many of these effects are mediated via FGF21-signalling in the hypothalamus. This defined a liver–neuroendocrine axis for the systemic adaptation to fasting. The work also enabled us to shed light on the apparently counterintuitive observation that pharmacological administration of FGF21 causes weight-loss in obese animals. We showed that this is also due to central FGF21-signalling. Specifically, it stimulates sympathetic nerve activity and this increases energy expenditure via the brown adipose tissue. We are currently investigating the fascinating effects of FGF21 on mood and reward-behaviour. In summary, significant and rapid progress has been made in understanding the physiological actions of this recently-identified hormone. On-going clinical trials will soon determine the potential of FGF21-based therapy for the treatment of obesity, and its complications, in humans