Oral Presentation Australian and New Zealand Obesity Society Annual Scientific Conference 2023

Interaction between GDF15 and leptin pathways to reduce body weight and adiposity (97935)

Vicky Tsai 1 , Rakesh Manandhar 2 , Michelle Lee-Ng 2 , Hong-Ping zhang 2 , David Brown 3 , Samuel N Breit 1
  1. St Vincent's Centre for Applied Medical Research and University of New South Wales, Sydney, NSW, Australia
  2. St Vincent's Centre for Applied Medical Research, Darlinghurst, NSW, Australia
  3. The Centre for Allergy and Immunology Research, University of Sydney and NSW Health Pathology, Sydney, NSW, Australia

GDF15 regulates body weight and appetite. In standard chow mice, treatment with recombinant GDF15 reduces body weight, fat mass, and lean mass. However, obese mice experienced a greater weight loss, mainly losing fat. GDF15 acts through neurons in the hindbrain area postrema (AP) and nucleus of the solitary tract (NTS), where its receptor, GFRAL, is found. The neural circuits and mechanisms engaged by the GDF15-GFRAL aren't completely clear. Obese mice treated with GDF15 showed greater weight and fat loss, suggesting GDF15's actions might involve other appetite regulators like leptin. Our research indicates GDF15 interacts with the leptin pathway.

To examine the impact of leptin on the action of GDF15 in body weight and adiposity, metabolic measurements were performed on: 1) HFD-induced obese male 28-week-old mice each implanted with two 14-day mini-osmotic pumps, which separately infuse GDF15, leptin, GDF15 and leptin or the vehicle, 2) obese ob/ob mice infusion with GDF15 or vehicle, and 3) Normal chow-fed mice infused with the pegylated leptin antagonist PEG-SMLA as well as GDF15 or vehicle. Neuronal activation was evaluated by quantification of FOS and pERK immunoreactivity in the hindbrain region of normal or obese mice treated with an IP injection of vehicle, GDF15 or leptin alone or in combination.

In both HFD and normal mice, combined GDF15 and leptin treatment induced greater body weight and adiposity reduction compared to single treatment. The effect of GDF15 on body weight and adiposity is significantly reduced in leptin-deficient mice and in mice whose endogenous leptin action was inhibited. Further, increased FOS and pERK immunoreactive neurons in the hindbrain were observed in the combined GDF15 and leptin treated compared to that in single treatment. Overall, this study suggests that part of GDF15’s metabolic actions might be enhanced by interaction with the leptin signalling pathway.

  1. Samuel N. Breit, Rakesh Manandhar, Hong-Ping Zhang, Michelle Lee-Ng, David A. Brown, Vicky Wang-Wei Tsai. GDF15 enhances body weight and adiposity reduction in obese mice by leveraging the leptin pathway. 2023. Cell Metabolism. Vol 35, pages 1341-1355.e3 (https://doi.org/10.1016/j.cmet.2023.06.009)