Acute peripheral versus central inhibition of insulin receptors differentially alters cytokine and blood-brain barrier responses to an inflammatory stimulus.

The blood-brain barrier (BBB)'s role in protecting the brain from exposure to harmful circulating factors has led to its disruption being implicated in neurodegenerative diseases such as vascular dementia and Alzheimer's disease. Insulin resistance, defined by an impaired response to insulin, is a common feature of metabolic disorders and neurodegenerative diseases. Importantly, individuals can possess peripheral insulin resistance independent of central insulin resistance and vice versa. States of insulin resistance, like diabetes mellitus for peripheral insulin resistance and Alzheimer's disease for central insulin resistance, are associated with inflammation and BBB disruption. However, the contributions of acute impairment of insulin receptor signaling solely in the periphery versus the brain to inflammation and BBB disruption are not clear. As central vs peripheral insulin resistance could have different effects on inflammation, we characterized the effects of acute central versus peripheral insulin receptor inhibition with or without an inflammatory insult, using lipopolysaccharide (LPS) as a prototypic immune stimulus. Male CD-1 mice were treated with an insulin receptor antagonist (S961), peripherally (intraperitoneal) or centrally (intranasal). This treatment was then followed by an intraperitoneal administration of either saline or LPS 30 min later, at a single 3 mg/kg dose known to cause inflammation and BBB disruption. Assays of BBB disruption and brain and serum collection were done 28 h after the injections. Metabolic hormones, cytokines, and the acute phase protein serum amyloid a (SAA) were then measured in serum and brain homogenates. In the absence of LPS, central S961 reduced serum hormones including ghrelin, gastric inhibitory peptide (GIP), and glucagon. Peripheral S961 significantly increased many cytokines in both brain and blood, whereas central S961 decreased serum SAA and increased a few cytokines. BBB integrity was not affected by S961 alone, but central S961 decreased LPS-induced BBB disruption and also lowered serum levels of SAA. These findings highlight the differential effects of peripheral versus central insulin receptor inhibition on cytokine responses and BBB integrity in the presence and absence of acute inflammation, elucidating differences in the molecular mechanisms for insulin receptor signaling depending on the location of signaling dysfunction. The results suggest a potential neuroprotective role of acute central insulin inhibition during acute inflammation.