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Review
. 2023 Jan 11;24(2):1422.
doi: 10.3390/ijms24021422.

Recent Advances in the Knowledge of the Mechanisms of Leptin Physiology and Actions in Neurological and Metabolic Pathologies

María E Casado  1   2 , Roberto Collado-Pérez  1 , Laura M Frago  1   2   3 , Vicente Barrios  1   2
Affiliations
Review

Recent Advances in the Knowledge of the Mechanisms of Leptin Physiology and Actions in Neurological and Metabolic Pathologies

María E Casado et al. Int J Mol Sci. .

Abstract

Excess body weight is frequently associated with low-grade inflammation. Evidence indicates a relationship between obesity and cancer, as well as with other diseases, such as diabetes and non-alcoholic fatty liver disease, in which inflammation and the actions of various adipokines play a role in the pathological mechanisms involved in these disorders. Leptin is mainly produced by adipose tissue in proportion to fat stores, but it is also synthesized in other organs, where leptin receptors are expressed. This hormone performs numerous actions in the brain, mainly related to the control of energy homeostasis. It is also involved in neurogenesis and neuroprotection, and central leptin resistance is related to some neurological disorders, e.g., Parkinson's and Alzheimer's diseases. In peripheral tissues, leptin is implicated in the regulation of metabolism, as well as of bone density and muscle mass. All these actions can be affected by changes in leptin levels and the mechanisms associated with resistance to this hormone. This review will present recent advances in the molecular mechanisms of leptin action and their underlying roles in pathological situations, which may be of interest for revealing new approaches for the treatment of diseases where the actions of this adipokine might be compromised.

Keywords: adipokine; biochemical mechanisms; biomarkers; cancer; inflammation; leptin; metabolic regulation; microRNA; molecular biology; obesity.

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Conflict of interest statement

The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results.

Figures

Figure 1
Figure 1
Multiple signaling pathways of leptin and its downstream effectors. ObRb oligomerization (for the clarity of the figure, only dimerization it is shown) activates JAK2/STAT3, PI3K, and ERK pathways. Activated JAK2 kinase induces Tyr residues of ObRb, that activates STAT-3 and -5. ObRb phosphorylation recruits SHP2 and Grb2 and increases ERK signaling. Crosstalk of leptin and insulin signaling is represented by the shaded area. See Section 2.1 for details.
Figure 2
Figure 2
Schematic signaling pathways of leptin in obesity. The upper panel (A) represents a normal situation (left) and another with hyperleptinemia (right) and its effect on the expression of hypothalamic neuropeptides that regulate intake. The panel (B) shows adipose tissue in lean (left) or obese patients (right). The adipose tissue in obese subjets presents a hypertrophy of adipocytes, as well as a greater infiltration of macrophages and other inflammatory cells. In panel (C), the mechanism involved in the endoplasmic reticulum stress blocking of leptin signaling is indicated. See Section 2.1 and Section 3.2.1 for details.
Figure 3
Figure 3
Schematic leptin signaling pathways involved in cancer. Phosphorylation of JAK2 and Akt activate ERK pathway that phosphorylates AP-1, increasing translation of VEGF, IL-1, and MCP-1, among other proinflammatory cytokines. See Section 2.1 and Section 3.2.3 for details.
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