Obesity is a chronic disease with epidemic proportions, and it causes serious threats for human health and wellbeing. Obesity results from long-term positive energy balance, and is characterized by excessive fat accumulation. Insulin action in the brain regulates feeding behaviour and whole-body energy balance in interplay with peripheral metabolic organs. In addition, endocannabinoid system in brain and periphery modulates appetite and energy homeostasis.

Obesity is associated with increased brain insulin-simulated glucose uptake (BGU), which is turn is linked with impaired insulin suppression of hepatic glucose production (EGP) and adipose tissue lipolysis. Subjects with obesity also exhibit lower endocannabinoid type 1 receptor (CB1R) availability in brain and abdominal adipose tissue. It remains unsolved, whether these alterations are present already before the development of obesity.

The aim of this thesis was to examine whether brain and peripheral tissue insulin sensitivity and CB1R availability are altered already in pre-obese state. We studied healthy non-obese young men with either high or low obesity risk using positron emission tomography. Tissue glucose uptake was quantified with a glucose analogue radiotracer [18F]FDG during hyperinsulinemic-euglycemic clamp, and CB1R availability with CB1R inverse agonist radioligand [18F]FMPEP-d2 . Insulin-stimulated BGU was increased in high as compared to low obesity risk subjects, and it was associated with decreased whole-body glucose uptake and increased insulin-suppressed EGP and serum free fatty acid levels. Familial obesity risk was associated with increased BGU. Abdominal adipose tissue CB1R availability was lower in high than low obesity-risk subjects, and associated with enlarged mass and decreased insulin sensitivity of abdominal adipose tissue. Lower cerebral CB1R availability was associated with decreased whole-body insulin sensitivity, enlarged visceral adipose tissue mass and higher levels of circulating endocannabinoids.

Altogether, these results show that altered brain insulin action and crosstalk with periphery, as well as dysregulated endocannabinoid signalling may precede obesity.