Leptin resistance

Light-sheet fluorescence microscopy (A,B) with infrared labelling of recombinant leptin visualizes the transport of leptin from the choroid plexus (CP) and median eminence (ME) to the arcuate nucleus (ARC) of mice. Densitometric analyses of leptin (C) and p-STAT3 (D) from Western blots (E) of the ARC of Chow-fed lean and HFD-fed obese mice subjected to saline (S) or leptin (L; 3 mg/kg BW, 45 min; n=3). *p<0.05 (t-test).

Novel pathways and circuits in hypothalamic leptin signaling

Leptin is an adipocyte derived hormone that governs the hypothalamic control of food intake and body weight. Leptin is secreted in direct proportion to fat mass, and targets leptin receptors (LepR) in the hypothalamus and downstream JAK2/STAT3, MAPK and PI3K signalling to regulate food intake and energy expenditure. Obese individuals have high leptin levels but are "leptin resistant", i.e. therapy with recombinant leptin is inefficient in decreasing food intake or body weight. 

Our lab aims to uncover the molecular underpinnings for leptin resistance. Our work recently had focused on blood brain barrier transport of leptin, and is now centred on characterising the molecular actions of leptin or leptin sensitizers such as celastrolon the proteome and transcriptome of different hypothalamic subpopulations.

Ultimately, it is our goal to delineate the mechanisms of leptin resistance, assess the exact mechanism of leptin sensitization by pharmacological agents, and identify novel leptin signalling components and novel leptin sensitizing weight loss drugs.

Daily injections of 100 µg/kg of the plant derived leptin sensitizer celastrol induces weight loss in obese mice (Pfuhlmann et al. Diabetes 2018).