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Mechanisms of reduced leptin-mediated satiety signaling during obesity

International Journal of Obesity volume 46, pages 1212–1221 (2022)Cite this article

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Abstract

Background/Objectives

Disrupted leptin signaling in vagal afferent neurons contributes to hyperphagia and obesity. Thus, we tested the hypothesis that intrinsic negative regulators of leptin signaling, suppressor of cytokine signaling 3 (SOCS3) and protein tyrosine phosphatase 1B (PTP1B) underlie dysfunctional leptin-mediated vagal afferent satiety signaling during obesity.

Methods

Experiments were performed on standard chow-fed control mice, high-fat fed (HFF), or low-fat fed (LFF) mice. SOCS3 and PTP1B expression were quantified using western blot and quantitative PCR. Nodose ganglion neuronal excitability and jejunal afferent sensitivity were measured by patch clamp and extracellular afferent recordings, respectively.

Results

Increased expression of SOCS3 and PTP1B were observed in the jejunum of HFF mice. Prolonged incubation with leptin attenuated nodose ganglion neuronal excitability, and this effect was reversed by inhibition of SOCS3. Leptin potentiated jejunal afferent nerve responses to CCK in LFF mice but decreased them in HFF mice. Inhibition of SOCS3 restored impaired vagal afferent neuronal excitability and afferent nerve responses to satiety mediators during obesity. Two-pore domain K+ channel (K2P) conductance and nitric oxide (NO) production that we previously demonstrated were elevated during obesity were decreased by inhibitions of SOCS3 or PTP1B.

Conclusions

This study suggests that obesity impairs vagal afferent sensitivity via SOCS3 and PTP1B, likely as a consequence of obesity-induced hyperleptinemia. The mechanisms underlying leptin resistance appear also to cause a more global impairment of satiety-related vagal afferent responsiveness.

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Fig. 1: SOCS3 and PTP1B expression were increased in HFF mice jejunum.
Fig. 2: Leptin attenuated the excitability of nodose ganglion neurons and this was recovered by inhibitions of SOCS3.
Fig. 3: Inhibition of SOCS3 and PTP1B restored nodose neuron excitability in HFF mice.
Fig. 4: Leptin potentiated CCK signaling in LFF mice whereas inhibited it via SOCS3 regulation in HFF mice.
Fig. 5: Inhibition of SOCS3 increased afferent responses to CCK and 5-HT in HFF mice.
Fig. 6: Inhibition of SOCS3 or PTP1B decreased K2P conductance and NO production in HFF mice.

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Acknowledgements

The authors wish to thank Iva Kosatka and Shumei He for their outstanding technical assistance and thank Dr Stephen Vanner, Dr David Reed, and Dr Alan Lomax for their helpful advice on this paper.

Funding

This study was funded by the Canadian Institute of Health Research (MOP 115021).

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Author notes

  1. These authors contributed equally: Sung Jin Park, Yang Yu.

Authors and Affiliations

  1. Gastrointestinal Diseases Research Unit, Queen’s University, Kingston, ON, K7L 2V7, Canada

    Sung Jin Park, Yang Yu, Carter G. Zides & Michael J. Beyak

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Contributions

MB supervised the project and obtained grant support. SP, YY, CZ, and MB designed the research. SP, YY, and CZ acquired and analyzed the data. YY, SP, CZ, and MB interpreted the data, drafted, and revised the paper.

Corresponding author

Correspondence to Michael J. Beyak.

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Competing interests

The authors declare no competing interests.

Ethics approval

All experiments were performed under an approved protocol (2014-1496) in accordance with the guidelines from the Queen’s University Animal Care Committee and Canadian Council for Animal Care.

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Park, S.J., Yu, Y., Zides, C.G. et al. Mechanisms of reduced leptin-mediated satiety signaling during obesity. Int J Obes 46, 1212–1221 (2022). https://doi.org/10.1038/s41366-022-01079-2

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