GDF15 enhances body weight and adiposity reduction in obese mice by leveraging the leptin pathway

Samuel N Breit; Rakesh Manandhar; Hong-Ping Zhang; Michelle Lee-Ng; David A Brown; Vicky Wang-Wei Tsai

doi:10.1016/j.cmet.2023.06.009

GDF15 enhances body weight and adiposity reduction in obese mice by leveraging the leptin pathway

Cell Metab. 2023 Aug 8;35(8):1341-1355.e3. doi: 10.1016/j.cmet.2023.06.009. Epub 2023 Jul 10.

Authors

Samuel N Breit¹, Rakesh Manandhar², Hong-Ping Zhang², Michelle Lee-Ng², David A Brown³, Vicky Wang-Wei Tsai⁴

Affiliations

¹ St Vincent's Centre for Applied Medical Research, St Vincent's Hospital, Sydney and University of New South Wales, Sydney, NSW 2010, Australia. Electronic address: s.breit@unsw.edu.au.
² St Vincent's Centre for Applied Medical Research, St Vincent's Hospital, Sydney and University of New South Wales, Sydney, NSW 2010, Australia.
³ Westmead Institute for Medical Research and Department of Immunopathology, Institute for Clinical Pathology and Medical Research-New South Wales Health Pathology Westmead Hospital and University of Sydney, Sydney, NSW 2145, Australia; The Centre for Allergy and Medical Research, The Westmead Institute for Medical Research, University of Sydney, Sydney, NSW 2145, Australia.
⁴ St Vincent's Centre for Applied Medical Research, St Vincent's Hospital, Sydney and University of New South Wales, Sydney, NSW 2010, Australia. Electronic address: v.tsai@amr.org.au.

PMID: 37433299
DOI: 10.1016/j.cmet.2023.06.009

Abstract

GDF15 regulates its anorexic effects through the hindbrain area postrema (AP) and nucleus of the solitary tract (NTS) neurons where its receptor, glial-derived neurotrophic factor receptor alpha-like (GFRAL), is expressed. The actions of GDF15 may interact with other appetite regulators elevated in obesity, such as leptin. Here, we report that in mice with high-fat-diet-induced obesity (HFD), the combined infusion of GDF15 and leptin causes significantly greater weight and adiposity loss than either treatment alone, indicating potentiation between GDF15 and leptin. Furthermore, obese, leptin-deficient ob/ob mice are less responsive to GDF15, as are normal mice treated with a competitive leptin antagonist. GDF15 and leptin induce more hindbrain neuronal activation in HFD mice than either treatment alone does. We report extensive connections between GFRAL- and LepR-expressing neurons and find LepR knockdown in the NTS to reduce the GDF15-mediated activation of AP neurons. Overall, these findings suggest that leptin signaling pathways in the hindbrain increase GDF15's metabolic actions.

Keywords: GDF15; GFRAL; adiposity; appetite; area postrema; body weight; hindbrain; leptin; nucleus of solitary tract; obesity.

MeSH terms

Adiposity*
Animals
Body Weight
Leptin* / metabolism
Leptin* / pharmacology
Mice
Mice, Obese
Obesity / metabolism
Receptors, Leptin / metabolism
Solitary Nucleus / metabolism

Substances

Leptin
Receptors, Leptin
Gdf15 protein, mouse