The role of the endocannabinoid system in the regulation of energy balance

PhD ceremony: mw. A.H. Koolman, 14.45 uur, Academiegebouw, Broerstraat 5, Groningen

Thesis: The role of the endocannabinoid system in the regulation of energy balance

Promotor(s): prof.dr. F. Kuipers, prof.dr. G. van Dijk, prof.dr. P.J.J. Sauer

Faculty: Medical Sciences

Contact: UMCG spokesperson, tel. +3150-361 2200, e-mail: voorlichting bvl.umcg.nl

In most mammalian species, including humans and rodents, the pattern of food intake is characterized by specific meals that are interspaced by periods of varying duration. This is allowed because ingested nutrients can be stored in the form of glycogen and triglycerides which buffer the flow of fuels that maintain ongoing cellular oxidative phosphorylation. Several signalling and effector systems are essential to maintain energy balance and fuel homeostasis over prolonged periods of time.

Over the last two decades, knowledge on mechanisms that regulate energy balance and fuel compartmentalization and metabolism has truly exploded. A recently discovered system involved in this regulation is the endocannabinoid system (ECS). This system consists of cannabinoid receptors (i.e., CB1- and CB2-receptors), endogenous ligands for these receptors called endocannabinoids and enzymes involved in synthesis and degradation of endocannabinoids. Among many functions, the ECS was found to be involved in regulation of food intake via the CB1-receptor.

Studies in animals and humans showed that blockade of CB1-signalling causes temporal reduction in food intake and sustained reduction in body weight gain. When the reduced daily food intake of CB1-receptor deficient (CB1-/-) mice was forced onto wild type (WT) mice for several weeks, CB1-/- mice were still leaner than WT mice. This demonstrates that CB1-mediated effects on body weight are partly independent of food intake and suggests that the ECS not only plays a pivotal role in regulation of feeding behaviour, but also in modulation of peripheral metabolism. Moreover, CB1-blockade causes prevention of lipid accumulation in the bloodstream and in the liver, which are risk factors for development of hepatic steatosis, atherosclerosis, and insulin resistance, all components of the metabolic syndrome.1-3 Since these effects are observed independently of weight loss, they support the notion that regulation of peripheral metabolism contributes to the metabolic effects of endocannabinoid signalling.

The aim of the work described in this thesis was to explore involvement of the ECS in modulation of energy balance in mice and, more specifically, the effects of endocannabinoid signalling in fuel partitioning and metabolism.