Low-Dose Lithium as a Therapy for High-Fat Diet Induced Obesity: A Burning Topic in Metabolic Research and Adipose Tissue Browning

Abstract

The prevalence of obesity is rising at an alarming rate around the globe. As a way to combat obesity, the activation of white adipose tissue thermogenesis has been a burning topic in metabolic research. Recent findings from our lab demonstrate that this thermogenic program is inhibited by a protein kinase known as glycogen synthase kinase 3-β (GSK3β); and the inhibition of GSK3β provides a mechanism to activate adipose tissue browning. Lithium (Li) is a well-known inhibitor of GSK3β and also a known sensitizer of insulin signalling. Our previous work has demonstrated that low dose lithium inhibits GSK3β and induces adipose browning in healthy male chow-fed mice. The purpose of this thesis was to examine the efficacy of low-dose lithium supplementation to inhibit adipose tissue GSK3β to activate the browning process to overcome the effects of high-fat diet (HFD) induced obesity and insulin resistance. 72 male C57BL/6J mice were divided into three experimental groups: 1) control (CON; n=24), 2) HFD (60% fat; n=24), and 3) HFD supplemented with a low-dose of lithium in their drinking water (10mg/kg body weight/day; HFD+Li; n=24) for 12 weeks. Inguinal white adipose tissue (iWAT), epididymal white adipose tissue (eWAT), and interscapular brown adipose tissue (BAT) were collected and underwent western blot and histological analysis. Lithium supplementation did not blunt the diet induced gain in body mass with the HFD. However, the HFD+Li mice ingested more calories than the HFD mice indicative of decreased metabolic efficiency. Lithium supplementation blunted the initial spike in a glucose tolerance test but exhibited no effects on insulin sensitivity at the whole body or tissue specific level. Lithium supplementation did not blunt the HFD induced reduction in GSK3β inhibition (Ser9) in iWAT, however, in eWAT the HFD+Li mice demonstrated higher GSK3β inhibition. Additionally, mitochondrial markers such as PGC-1α and cytochrome C were higher in HFD+Li eWAT compared to control, with cytochrome C being higher compared to HFD mice. This data provides evidence that low-dose lithium supplementation alone can increase the thermogenic program in visceral WAT depots but may not be robust enough to increase thermogenesis in subcutaneous WAT depots under HFD conditions.