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Review
. 2024 Jan 17;25(2):1137.
doi: 10.3390/ijms25021137.

Molecular and Cellular Mechanisms Underlying the Cardiac Hypertrophic and Pro-Remodelling Effects of Leptin

Morris Karmazyn  1 , Xiaohong Tracey Gan  1
Affiliations
Review

Molecular and Cellular Mechanisms Underlying the Cardiac Hypertrophic and Pro-Remodelling Effects of Leptin

Morris Karmazyn et al. Int J Mol Sci. .

Abstract

Since its initial discovery in 1994, the adipokine leptin has received extensive interest as an important satiety factor and regulator of energy expenditure. Although produced primarily by white adipocytes, leptin can be synthesized by numerous tissues including those comprising the cardiovascular system. Cardiovascular function can thus be affected by locally produced leptin via an autocrine or paracrine manner but also by circulating leptin. Leptin exerts its effects by binding to and activating specific receptors, termed ObRs or LepRs, belonging to the Class I cytokine family of receptors of which six isoforms have been identified. Although all ObRs have identical intracellular domains, they differ substantially in length in terms of their extracellular domains, which determine their ability to activate cell signalling pathways. The most important of these receptors in terms of biological effects of leptin is the so-called long form (ObRb), which possesses the complete intracellular domain linked to full cell signalling processes. The heart has been shown to express ObRb as well as to produce leptin. Leptin exerts numerous cardiac effects including the development of hypertrophy likely through a number of cell signaling processes as well as mitochondrial dynamics, thus demonstrating substantial complex underlying mechanisms. Here, we discuss mechanisms that potentially mediate leptin-induced cardiac pathological hypertrophy, which may contribute to the development of heart failure.

Keywords: autophagy; cardiac hypertrophy and remodelling; heart failure; intracellular signalling; leptin; mitochondrial dynamics.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
Leptin receptor subtypes. Six different isoforms of ObR have been identified, denoted as ObRa, ObRb, ObRc, ObRd, ObRe, and ObRf. Each receptor subtype shares two cytokine-binding homology regions (CHR1 and CHR2) with CHR2 representing the main binding site for leptin, an IgG-like domain, and two fibronectin type 3 domains (FN3) within its C-terminal. All isoforms have transmembrane regions except the ObRe receptor, which functions as a soluble leptin binding receptor not anchored to the cell membrane and which binds circulating leptin, thereby regulating leptin bioavailability and functionality but is unable to transduce any downstream signalling. The intracellular N-terminal domain expresses a BOX-1 motif, which is critical for JAK-2 binding. The OBRb receptor is the only long isoform to also express a BOX-2 motif, which facilitates the activation of the JAK2/STAT transduction pathway. Moreover, ObRb contains 3 tyrosine residues (Tyr986, Tyr1076, and Tyr1141) whose phosphorylation enables STAT3/STAT5 activation. The short isoforms ObRa,c,d,f have only one intracellular domain (Box 1) and therefore limited signalling capacity. Created with PowerPoint software (Microsoft Office 365).
Figure 2
Figure 2
Activation of the JAK/STAT pathway by leptin. Binding of leptin to ObRb on target cells results in receptor dimerization, which results in the ability of associated JAKs to phosphorylate one another. These trans-phosphorylated JAKs can now phosphorylate a number of targets including STATs, which can now enter the nucleus and regulate the transcription of target genes. Created with BioRender.com.
Figure 3
Figure 3
Primary sources of leptin production, which can exert cardiac effects including circulating adipocyte-derived leptin as well as locally produced leptin, functioning in a paracrine or autocrine manner and stimulated by pro-hypertrophic factors including angiotensin II or endothelin-1. Created with BioRender.com.
Figure 4
Figure 4
Potential cellular events underlying the pro-hypertrophic effects of leptin as discussed in this review. Created with BioRender.com.
Figure 5
Figure 5
Leptin-induced caveolae-dependent activation of RhoA/ROCK and its contribution to the hypertrophic program. CM, cell membrane; GEFs, guanine nucleotide exchange factors; LIMK, LIM kinase. Created with BioRender.com.
Figure 6
Figure 6
Mitochondrial dynamics in terms of fusion and fission and the pro-fission effect of leptin. Mfn 1 and 2 and Opa1 are pro-fusion proteins mitofusin 1 and 2 and optic atrophy 1 protein, respectively. Drp1 and Fis1 are pro-fission proteins dynamin-related protein 1 and mitochondrial fission protein 1, respectively. Created with BioRender.com.
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