Oral Presentation ANZOS Annual Scientific Meeting 2021

Leptin is a key regulator of glucose homeostasis in obesity (#18)

Stephanie E Simonds 1 , Jack T Pryor 1 , Michael A Cowley 1
  1. Monash University, Clayton, Vic, Australia

Approximately 9 out of 10 people with type-2 diabetes are overweight. Leptin is a hormone secreted from white fat cells that exerts control over both food intake and energy expenditure. Recently we described the central mechanisms underlying the hypertensive effects of hyperleptinemia in obesity. Work presented here used continuous radiotelemetric glucose monitoring in mice in combination with multiple gold standard techniques in order to determine the effects of dorsomedial hypothalamic (DMH) leptin signalling on peripheral glucose control. A leptin receptor (LepR) antagonist administered directly into the brain impaired DIO mouse glucose tolerance demonstrating that leptin retains the ability to regulate blood glucose concentration in obesity. Knockdown of DMH LepR function using short hairpin adeno-associated virus (AAV) RNA significantly reduced brown adipose tissue (BAT) thermogenesis by -0.8 ± 0.1°C and increased basal blood glucose (14.3 ± 0.6mmol/l to 9.4 ± 0.5mmol/l) and impaired glucose tolerance. Conversely, chemogenic activation of LepR-expressing DMH neurons significantly elevated BAT thermogenesis (1.5 ± 0.2 °C increase). This increased BAT temperature was immediately followed by a decrease in plasma blood glucose concentration (7.6 ± 0.5 mmol/l to 5.8 ±0.5 mmol/l). Work presented here demonstrates that increasing the activity of LepR expressing neurons in the DMH can improve glucose tolerance in obesity though an elevation of BAT metabolic activity.