Bypassing UCP-1 Mediated Thermogenesis Ameliorates Cognitive Impairment in Early Prediabetes

Abstract ID 96579 Poster Board 108 Prediabetes is an early stage of metabolic dysfunction characterized by impaired glucose tolerance and marked insulin resistance associated with an increased risk of vascular diseases. Notably, a strong correlation between this metabolic dysfunction and reduced cerebral blood flow has been established. Cerebral hypoperfusion is known to lead to vascular cognitive impairment (VCI) and poor memory performance as well. Additionally, hyper-anxiety-like behavior and markedly impaired spatial learning abilities are also linked to prediabetes. In our previous work, we developed a high fat diet (HFD)-fed prediabetic rat model that showed mild cognitive impairment. These rats showed elevated expression of uncoupling protein 1 (UCP1) in select adipose tissue depots associated with increased thermogenic energy dissipation and a higher oxygen consumption leading to hypoxia that triggers adipose inflammation and the ensuing cerebrovascular impairment. We also showed that UCP1 inhibition not only ameliorated adipose tissue inflammation, but also corrected the associated cardiovascular deficit. Here, we investigated the effect of limiting UCP1-mediated thermogenesis either by inhibiting UCP1 by inorganic phosphate supplementation or by enhancing futile creatine phosphate cycling as an alternative thermogenesis pathway associated with lower oxygen consumption rate on cognitive function in prediabetic rats. In this regard, male Sprague Dawley rats were randomized among control and HFD-fed prediabetic groups. Following 10 weeks of HFD-consumption, animals were further randomized to receive either no treatment, creatine monohydrate, inorganic phosphate or pioglitazone. Caloric intake, blood glucose level and body weight were recorded regularly. Prior to sacrifice, rats underwent a battery of behavioral tests (Novel object recognition NOR, Y-maze, Open field test OFT, Elevated Plus Maze test EPM) to assess their cognitive, memory, and locomotor functions as well as anxiety disorders. After sacrifice, serum and tissue samples were stored at −80 °C for further analysis. Current findings show that by passing UCP1-mediated thermogenesis either via inorganic phosphate or creatine supplementation can potentially mitigate the negative impact of HFD-induced adipose inflammation on cognitive function. These treatments reversed the observed cognitive decline and memory deficits in early metabolic impairment in a manner equivalent to pioglitazone administration that is known to mitigate adipose tissue inflammation. Further examination is under way to confirm the impact on molecular and inflammatory pathways underlying this effect.