Brain insulin action regulates metabolism and behavior. Conversely in diabetes, brain insulin resistance associates with obesity and behavioral abnormalities. Intranasal insulin (INI) treatment activates brain insulin signaling in rodents and humans with a more prominent effect on metabolism in males. Recently, we have shown that INI treatment reduces diet-induced high fat diet (HFD) weight gain in males. Here, we investigated whether INI treatment reduces metabolic and behavioral abnormalities in males and females fed a HFD.

We investigated the effect of 1h 1.75U INI treatment on metabolism and behavior in 12 weeks old C57BL/6N male and female mice fed a normal chow diet (NCD) and HFD for two weeks. We analyzed brain insulin signaling using ELISA, qPCR and western blot technique and assessed metabolic parameters as well as behavior using a dark-light box and novelty-suppressed feeding test.

We show that acute INI treatment activates the insulin cascade in a region-dependent manner with highest activation in olfactory bulbus, caudate putamen and hypothalamus in males. INI treatment caused a two-fold increase in insulin levels in the cerebrospinal fluid (CSF) without altering blood glucose and insulin levels. INI reduced anxiety in males fed a NCD using a dark-light box test and novelty-suppressed feeding test. Yet, INI treatment did not alter insulin signaling and behavior in mice fed a HFD. Though male and female mice exhibited equal amounts of insulin receptor signaling proteins in the brain, INI treatment did not alter food intake, body weight gain or behavior in females fed a NCD or a HFD. In females, basal insulin levels in the CSF were comparable to insulin levels of INI-treated males and did not drastically increase further after INI treatment indicating optimal insulin action under basal conditions. Overall, we show that INI treatment activates the insulin signaling throughout the brain and improves in a sex-dependent manner metabolism and behavior only in healthy conditions.


C. Chudoba: None. A. Kleinridders: None.


German Federal Ministry of Education and Research; State of Brandenburg (82DZD00302)

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