Central role of the adipokine chemerin in energy balance regulation and neuroinflammation

Multiple factors related to modern lifestyle, such as sedentary behaviour and overconsumption calorie-dense foods disrupt energy homeostasis and facilitate weight gain. Homeostatic regulation of food intake and energy expenditure results from a complex series of interactions of hormones and neuromodulators in the hypothalamus of the central nervous system to regulate appetite homeostasis.

Among the hormones driving this circuitry that link to unwanted effects of modern living is the adipokine chemerin. Chemerin is an adipokine involved in inflammation, adipogenesis, angiogenesis and energy metabolism. In humans affected by obesity chemerin gene expression in peripheral tissues and circulating levels are elevated. Chemerin is proposed as a link between obesity and the development of type-2 diabetes. In mice, plasma levels of chemerin are upregulated by high-fat (HF) feeding and gain and loss of function studies show an association of chemerin with body weight, food intake and glucose homeostasis independent of diet. Therefore, chemerin is an important blood-borne mediator that, amongst its other functions, controls appetite and body weight. Like other adipokines such as leptin, chemerin has proinflammatory effects that are likely to be important in its central actions. Almost all studies of chemerin to date have focussed on its release from adipose tissue and its effects on peripheral tissues with the central effects largely overlooked. Recently we identified a novel central role for chemerin showing that central administration of chemerin into the third ventricle of the hypothalamus increased body weight and food intake and altered gene expression of neuropeptides involved in feeding behaviours.

The aim of this PhD project is to understand the role of chemerin in the regulation of appetite and body weight. Since chemerin is linked with obesity, the research will inform our understanding of fundamental mechanisms underlying lifestyle factors (e.g. high fat diet) and obesity. This understanding is needed to develop avoidance obesity strategies or appropriate therapies, meeting a priority health challenge of our time.

Hypothesis and aims

In obesity, chemerin circulating levels are increased. Central chemerin infusion results in hypothalamic remodelling by actions on hypothalamic glial cells [Helfer et al, 2016]. Our data support the hypothesis that chemerin, a hormone linking high fat diet to obesity, activates hypothalamic glial cells causing neuroinflammation. In turn neuroinflammation causes dysregulation of neuronal activity of neurons in the circuits involved in appetite and body weight. To test this hypothesis, the aims of the PhD project are:

• to determine the subtypes and cellular expression of chemerin receptors mediating the hypothalamic effects of chemerin in appetite and body weight regulation.
• to test the idea that central chemerin causes microglial-mediated neuroinflammation in the hypothalamus to disrupt endocrine functions and glucose homeostasis.