The binding of leptin to its receptor, LepR, initiates multiple signaling cascades, including JAK2/STAT3, STAT5, IRS/PI3K, SHP2/MAPK, and AMPK/ACC pathways. Upon leptin binding, LepR undergoes dimerization, facilitating the recruitment of Janus kinase 2 (JAK2) to form a LepR/JAK2 complex. JAK2, a tyrosine kinase, provides essential phosphorylation functions necessary for downstream signaling.
Activated JAK2 undergoes autophosphorylation and also phosphorylates three critical tyrosine residues on LepR: Tyr985, Tyr1077, and Tyr1138. Phosphorylated Tyr1138 and Tyr1077 serve as docking sites for STAT3 and STAT5, respectively. These molecules bind to the phosphorylated residues and are subsequently phosphorylated by JAK2. The activated (phosphorylated) STAT3 and STAT5 then form dimers, each comprising two STAT3 or two STAT5 molecules as functional units. These dimers translocate to the nucleus to initiate transcription of target genes, leading to their expression. Many of these genes influence appetite and energy metabolism, enabling leptin signaling to induce anorexigenic effects (appetite reduction) and regulate energy homeostasis.
Among the target genes activated by STAT3 is suppressor of cytokine signaling 3 (SOCS3), which inhibits leptin signaling by binding to the phosphotyrosine residues (Tyr985) of LepR or directly interacting with JAK2. This interference prevents JAK2 from further activating STAT3, establishing a negative feedback mechanism to modulate signaling and prevent overstimulation. Additionally, protein tyrosine phosphatase 1B (PTP1B) contributes to signal inhibition by dephosphorylating JAK2.
Following JAK2 activation, SHP2 (a protein tyrosine phosphatase containing SH2 domains) binds to the Tyr985 residue on LepRb. This interaction promotes recruitment of another adaptor protein, Grb2, which ultimately activates the MAPK signaling pathway. Besides MAPK, leptin signaling also involves the PI3K pathway, activated through phosphorylation of insulin receptor substrate (IRS). This pathway engages several downstream molecules, including FoxO1, mTOR, and PDE3B, regulating diverse cellular processes such as protein synthesis, cell growth, and energy metabolism.
Moreover, leptin modulates feeding and metabolic processes in the brain and peripheral organs through 5'-AMP-activated protein kinase (AMPK) and acetyl-CoA carboxylase (ACC). AMPK, an energy sensor, activates in response to low energy states, leading to appetite suppression and enhanced energy expenditure. This mechanism underscores leptin’s role in appetite regulation, weight control, and energy balance.
Despite the widespread distribution of leptin receptors, anatomical and functional evidence indicates that leptin primarily influences energy balance through its action on the brain. Receptor subtypes located elsewhere predominantly play roles in transport and/or clearance.
During starvation, as fat reserves are depleted, leptin levels drop significantly. This reduction triggers compensatory regulatory responses in the hypothalamus, especially within the arcuate nucleus, altering the expression of appetite-related neuropeptides. For instance, levels of neuropeptide Y (NPY) and agouti-related peptide (AgRP) increase, promoting appetite and feeding behavior to aid energy intake during energy deficiency. Concurrently, levels of pro-opiomelanocortin (POMC) and cocaine- and amphetamine-regulated transcript (CART) decrease. These molecules typically suppress appetite, with POMC’s derivative, α-melanocyte-stimulating hormone (α-MSH), acting on melanocortin receptors to reduce food intake. In a state of hunger, decreased leptin levels inhibit POMC and CART expression, reducing anorexigenic signaling and further stimulating appetite. Additionally, these neurons project signals to the lateral hypothalamus, regulating melanin-concentrating hormone (MCH), a potent orexigenic factor.
The decline in leptin levels also modulates multiple neuroendocrine axes to conserve energy. For example, it increases corticotropin-releasing hormone (CRH) secretion, leading to elevated cortisol levels, which support gluconeogenesis and energy availability. Reduced leptin levels also lower thyrotropin-releasing hormone (TRH), thereby decreasing thyroid hormone secretion and reducing basal metabolic rate to conserve energy. Additionally, growth hormone-releasing hormone (GHRH) and growth hormone (GH) secretion are modulated to adjust energy utilization within the body. These hormonal adjustments lower basal metabolic rate, reduce thermogenesis, and inhibit growth and reproductive functions, channeling energy towards essential metabolic processes, thus ensuring survival under starvation conditions.
Leptin depletion during starvation also suppresses immune function. Normally, leptin promotes T-cell activation and cytokine production, playing a critical role in immune regulation. However, in a state of nutrient deficiency, reduced leptin levels dampen these immune responses, achieving a dual purpose: conserving the high energy costs of immune activity and redirecting limited resources to basic metabolic functions. Although this immunosuppression temporarily reduces infection resistance, it prioritizes survival in nutrient-scarce environments.
In rodents, leptin's role in starvation adaptation is particularly vital, as these animals are highly sensitive to short-term nutrient scarcity. With a high metabolic rate and limited fat reserves, rodents exhibit rapid metabolic adaptations under low leptin conditions. These adaptations enable them to survive in starvation environments by suppressing non-essential functions, such as growth and reproduction, while enhancing feeding behaviors, thus increasing their chances of survival.