Leptin signaling and leptin resistance

doi:10.1007/s11684-013-0263-5

Front Med

2013, Vol. 7

Issue (2) : 207-222 https://doi.org/10.1007/s11684-013-0263-5

REVIEW

Leptin signaling and leptin resistance

Yingjiang Zhou¹(

), Liangyou Rui²(

)

1. Cambridge Laboratories, Pfizer Worldwide Research & Development, Cambridge, MA 02139, USA; 2. Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI 48109, USA

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Abstract

Leptin is secreted into the bloodstream by adipocytes and is required for the maintenance of energy homeostasis and body weight. Leptin deficiency or genetic defects in the components of the leptin signaling pathways cause obesity. Leptin controls energy balance and body weight mainly through leptin receptor b (LEPRb)-expressing neurons in the brain, particularly in the hypothalamus. These LEPRb-expressing neurons function as the first-order neurons that project to the second-order neurons located within and outside the hypothalamus, forming a neural network that controls the energy homeostasis and body weight. Multiple factors, including inflammation and endoplasmic reticulum (ER) stress, contribute to leptin resistance. Leptin resistance is the key risk factor for obesity. This review is focused on recent advance about leptin action, leptin signaling, and leptin resistance.

Keywords leptin signaling leptin receptor energy balance leptin resistance obesity

Corresponding Author(s): Zhou Yingjiang,Email:yingjiang.zhou@pfizer.com; Rui Liangyou,Email:ruily@umich.edu

Issue Date: 05 June 2013

Cite this article:

Yingjiang Zhou,Liangyou Rui. Leptin signaling and leptin resistance[J]. Front Med, 2013, 7(2): 207-222.

URL:

https://academic.hep.com.cn/fmd/EN/10.1007/s11684-013-0263-5
https://academic.hep.com.cn/fmd/EN/Y2013/V7/I2/207

Fig.1 Leptin signaling pathways. Leptin binds to LEPRb and activates JAK2. JAK2 phosphorylates LEPRb on Tyr, Tyr and Tyr. Phospho-Tyr, -Tyr and-Tyr bind to downstream molecules and activate the JAK2/STAT3, JAK2/STAT5, PI3K/IRS/AKT, and SHP2/ERK pathways. These pathways act coordinately to regulate energy balance and body weight. LEPRb signaling is regulated both negatively by SOCS3, PTP1B, TCPTP and PTEN and positively by SH2B1. Many factors, including hyperleptinemia, inflammation, endoplasmic reticulum (ER) stress, and defective autophagy, contribute to leptin resistance.

Fig.2 Leptin-targeted neurons and neural circuits. Leptin directly suppresses NPY/AgRP neurons and stimulates POMC/CART neurons in the ARC. ARC neurons project to multiple hypothalamic areas including the DMH, VMH, PVH, and LHA. Leptin also directly activates LEPRb in DMH, VMH, PVH, and LHA neurons. The PVH and LHA are important hypothalamic output pathways that mediate leptin’s anti-obesity action. VTA: ventral tegmental area; NTS: solitary nucleus; IML: intermediolateral cell column.

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