Leptin and adiponectin signaling pathways

The leptin and adiponectin signaling pathways constitute a central endocrine axis that regulates systemic energy balance, metabolic homeostasis, and inflammatory responses [1, 3]. Leptin, an adipokine primarily secreted by white adipose tissue, binds to the long isoform of the leptin receptor (LEPR or Ob-Rb) to activate the JAK2/STAT3, PI3K/Akt, and MAPK/ERK signaling cascades, which primarily function in the hypothalamus to suppress appetite and increase energy expenditure [12, 13, 18]. Conversely, adiponectin signals through its receptors, AdipoR1 and AdipoR2, to activate the AMP-activated protein kinase (AMPK) and peroxisome proliferator-activated receptor alpha (PPAR-alpha) pathways via the adaptor protein APPL1, thereby enhancing insulin sensitivity and fatty acid oxidation [1, 4, 12]. These two pathways often exhibit antagonistic crosstalk, with adiponectin exerting anti-inflammatory and anti-proliferative effects that counteract the pro-inflammatory and mitogenic actions of leptin [1, 2, 8]. Dysregulation of this axis, typically manifesting as hyperleptinemia with concomitant leptin resistance and hypoadiponectinemia, is a key driver of obesity-related pathologies, including type 2 diabetes, cardiovascular disease, and various cancers [1, 19, 20]. Therapeutic interventions targeting these pathways include leptin analogs like metreleptin for deficiency states, as well as investigational adiponectin agonists and leptin sensitizers aimed at restoring metabolic balance [11, 16, 18]. Additionally, downstream modulators of these pathways are being explored for their potential to inhibit oncogenic signaling in cancers where this axis is aberrant [1, 13, 16]. The balance between these two adipokines, often measured by the leptin-to-adiponectin ratio, serves as a critical biomarker for metabolic health and disease progression [3, 6, 19].

Other names

Adipocytokine signaling pathwayLeptin-adiponectin axisAdipokine signaling pathways

Leptin activates the JAK2/STAT3 pathway to regulate energy balance and the PI3K/Akt and MAPK pathways to influence cell survival and proliferation [12, 13]. Adiponectin activates AMPK and PPAR-alpha to promote glucose uptake and lipid oxidation while suppressing hepatic glucose production [1, 9]. Adiponectin also exerts antagonistic effects on leptin signaling by activating phosphatases like PTP1B and PP2A, which dephosphorylate key leptin signaling mediators such as JAK2, STAT3, and Akt [1, 2, 8].