Insulin sensitivity in mesolimbic pathways predicts and improves with weight loss in older dieters

Central insulin is involved in the regulation of hedonic feeding. Insulin resistance in overweight has recently been shown to reduce the inhibitory function of insulin in the human brain, but how this affects future weight management is unclear. Also unknown is the role of central insulin sensitivity on eating behavior of older people, who are highly vulnerable to hyperinsulinemia and in whom neural target systems of insulin action undergo age-related changes. Here, fifty overweight, pre-diabetic elderly participated in a double-blind, placebo-controlled pharmacological fMRI study before and after randomization to a 3-month caloric restriction or active waiting group. We show that treatment outcome in dieters can be predicted by baseline measures of individual intranasal insulin (INI) inhibition of value signals in the ventral tegmental area related to sweet food liking as well as, independently, by peripheral insulin sensitivity. At follow-up, both INI inhibition of hedonic value signals in the nucleus accumbens and whole-body insulin sensitivity improved with weight loss. These data highlight the critical role of central insulin function in mesolimbic systems for future weight management in humans and directly demonstrate that neural insulin function can be improved by weight loss even in older age, which may be essential for preventing metabolic disorders in later life.