Thermotherapy has Sexually Dimorphic Responses in APP/PS1 Mice

Abstract A thermoregulatory decline occurs with age due to changes in muscle mass, vasoconstriction, and metabolism that lowers core body temperature (Tc). Although lower Tc is a biomarker of successful aging, we have previously shown this worsens cognitive performance in the APP/PS1 mouse model of Alzheimer’s disease (AD) [1]. We hypothesized that elevating Tc with thermotherapy would improve metabolism and cognition in APP/PS1 mice. From 6-12 months of age, male and female APP/PS1 and C57BL/6 mice were chronically housed at 23 or 30°C. At 12 months of age, mice were assayed for insulin sensitivity, glucose tolerance, and spatial cognition. Plasma, hippocampal, and peripheral (adipose, hepatic, and skeletal muscle) samples were procured postmortem and tissue-specific markers of amyloid accumulation, metabolism, and inflammation were assayed. Chronic 30°C exposure increased Tc in all groups except female APP/PS1 mice. All mice receiving thermotherapy had either improved glucose tolerance or insulin sensitivity, but the underlying processes responsible for these effects varied across sexes. In males, glucose regulation was influenced predominantly by hormonal signaling in plasma and skeletal muscle glucose transporter 4 expression, whereas in females, this was modulated at the tissue level. Thermotherapy improved spatial navigation in male C57BL/6 and APP/PS1 mice, with the later attributed to reduced hippocampal soluble amyloid-β (Aβ)42. Female APP/PS1 mice exhibited worse spatial memory recall after chronic thermotherapy. Together, the data highlights the metabolic benefits of passive thermotherapy, but future studies are needed to determine therapeutic benefits for those with AD. Competing Interest Statement The authors have declared no competing interest. Footnotes This version of the manuscripts has been revised based upon reviewer feedback from the journal Aging. Abbreviations - Aβ - amyloid-β - AD - Alzheimer’s disease - AUC - area under the curve - B2M - beta-2- microglobulin - BAFF - B-cell activating factor - FGF21 - fibroblast growth factor 21 - Tcw - a 42-specific - G6PC - glucose 6-phosphatase - Gck - glucokinase - GLP1 - glucagon-like peptide 1 - Glut - glucose transporter - GTT - glucose tolerance test - InsR - insulin receptor - ip - intraperitoneal - ITT - insulin tolerance test - MWM - Morris water maze - pg - perigonadal - PGC - peroxisome proliferator-activated receptor-gamma coactivator - PI3K - phosphatidylinositol 3- kinase - Tc - core body temperature - TNF - tumor necrosis factor - UCP - uncoupling protein - VAT - visceral adipose tissue - WAT - white adipose tissue).