leptin

Overview

Leptin is a 16 kDa adipokine encoded by the LEP gene and secreted primarily by white adipose tissue. It functions as a critical hormonal signal in the regulation of energy homeostasis, appetite suppression, and body weight, acting principally through the leptin receptor (LEP-R) expressed in the hypothalamus and other brain regions. By signaling the brain about peripheral energy stores, leptin suppresses food intake and promotes energy expenditure — a axis that intersects broadly with insulin, glucagon-like peptide-1 (GLP-1), and AMPK pathways. Circulating leptin levels are proportional to adipose tissue mass, meaning individuals with obesity typically exhibit elevated plasma leptin alongside paradoxical leptin resistance, in which impaired transport across the blood-brain barrier and diminished central receptor signaling blunt the hormone's anorectic effects. At the cellular level, leptin receptor tyrosine kinase (RTK) signaling is negatively regulated by protein-tyrosine phosphatase 1B (PTP1B), and downstream pathways include JAK2/STAT3, PI3K/AKT, and AMPK cascades that coordinate glucose metabolism, immune function, and cell survival.

Beyond its classical role in metabolism, leptin exerts pleiotropic effects across reproductive biology, immune modulation, bone metabolism, cardiovascular regulation, and oncology. It influences inflammatory cytokine networks — interacting with interleukin-6 and C-reactive protein — and modulates coagulation. In placental biology, LEP expression serves as a marker of trophoblast function and metabolic adaptation during pregnancy. Leptin resistance, frequently co-occurring with insulin resistance and type 2 diabetes, is a central feature of obesity-related metabolic dysfunction, making leptin signaling a high-priority therapeutic target across endocrinology, diabetology, and oncology.

Focus of Latest Publications

Recent publications have examined leptin in a range of metabolic, inflammatory, and neuroendocrine contexts. In pregnancy research, leptin was evaluated as an adipokine potentially mediating improved maternal cardiovascular function after metabolic bariatric surgery, and placental transcriptome profiling in gestational diabetes mellitus found LEP to be downregulated in GDM placentas alongside broader changes in metabolic, extracellular matrix, ER stress, and immune-related pathways. Another pregnancy-focused study linked altered adipokine levels, including leptin, to maternal cardiac function following bariatric surgery.

Several studies addressed leptin in obesity-related metabolic regulation. In the EXERDIET-HTA trial, supervised aerobic exercise combined with a hypocaloric diet reduced serum leptin in adults with primary hypertension and overweight/obesity, with the decrease observed after 16 weeks and not maintained at 6 months; body mass index was the main independent correlate of leptin, and in women waist-to-hip ratio and fat-free mass also contributed to leptin variability. A preclinical study in male diabetic UCD-T2DM rats found that chronic recombinant leptin treatment reduced food intake and improved glucose homeostasis and insulin sensitivity without changing body weight, but did not alter gut microbiome composition, gut permeability, or colon epithelial hypoxic gradients. A computational model of the semaglutide-responsive gut-brain axis also included leptin and leptin sensitivity among the long-term metabolic variables used to generate hypotheses about appetite and weight regulation.

Leptin was also studied in inflammatory and pain-related disease. In critically ill COVID-19 patients, serum leptin was among the pro-inflammatory markers assessed for associations with coagulopathy, and statistically significant associations were reported between leptin levels and several coagulation parameters, including D-dimers, prothrombin time, prothrombin activity, activated partial thromboplastin time, and INR. In a reserpine-induced fibromyalgia rat model, fasudil was reported to suppress ObRb-linked JAK2/STAT3 hyperactivation and reduce pain behaviors, neuroinflammation, and macrophage-mediated immune activation, supporting leptin-JAK2/STAT3 signaling as a therapeutic target in chronic pain states.

Other work placed leptin within broader metabolic signaling networks. A study of cannabisin A and B from hemp seed hulls proposed improvement of glucose homeostasis through re-engagement of insulin, leptin, and AMPK pathways via selective PTP1B inhibition. In type 2 diabetic rats, psyllium husk research also listed leptin among metabolic regulators of interest in liver and muscle, although the abstract did not report leptin-specific outcomes.

Key Publications

Jun Role of Adipokines in Maternal Cardiac Function of Pregnancies Following Metabolic Bariatric Surgery. (Obesity surgery, 2026, PMID 42240794): "an altered adipokine (adiponectin and leptin) levels."
May Placental transcriptome profiling and immune signature differences in pregnancies with and without gestational diabetes mellitus: An observational study. (Medicine, 2026, PMID 42175401): "In contrast, LEP and ERBB2 were downregulated in GDM placentas."
Jun Aerobic Exercise Plus Hypocaloric Diet on Serum Leptin Concentrations in Adults With Primary Hypertension and Overweight/Obesity: Results From the EXERDIET-HTA Trial. (Clinical obesity, 2026, PMID 42082343): "to determine differences in [leptin] in physically inactive adults (n=69, 46.4% women) with HTN and living with overweight or obesity following a 16-week supervised aerobic exercise training (EX group, 2 days/week) intervention with an attention control (AC, only physical advice) group, both combined with a hypocaloric diet;"
May Cross-talk between inflammation and coagulation in severe COVID-19: Association of leptin and classical pro-inflammatory markers with coagulation disorders in a single-center observational cohort study. (Medicine, 2026, PMID 42065184): "Pro-inflammatory markers included leptin and classical biomarkers."
Jun SemaGBA: A System Dynamics Model of the Semaglutide-Responsive Gut-Brain Axis A Model of How the Brain and Semaglutide Regulate Appetite and Weight. (Diabetes, obesity & metabolism, 2026, PMID 41969210): "...generate hypotheses about semaglutide's long-term metabolic (body weight, net energy intake, blood glucose, insulin, insulin sensitivity, glucotoxicity, leptin, leptin sensitivity, lipotoxicity, GLP-1 and βcell function)..."
May Effects of Psyllium Husk on Metabolic Regulators, Insulin Resistance, and SIRT6 in Liver and Muscle of Type 2 Diabetic Rats. (Veterinary medicine and science, 2026, PMID 41940860): "Biomarkers like glucose transporter type 4 (GLUT4), phosphoinositide 3-kinase (PI3K), sirtuin 6 (SIRT6), nesfatin-1, glucagon-like peptide 1 (GLP-1), leptin, and insulin-like growth factor 1 (IGF-1) play important roles in various physiological processes."
Jun Anti-inflammatory and antinociceptive effects of fasudil in a reserpine-induced fibromyalgia model: Role of ROCK-regulated leptin-STAT3 signaling. (Life sciences, 2026, PMID 41942028): "Emerging evidence positions leptin and its downstream signaling networks as key regulators of nociceptive modulation and neuroinflammatory processes in chronic pain states."
May Improvement of glucose homeostasis during leptin treatment does not alter the intestinal microbiome in male diabetic UC Davis type-2 diabetes mellitus rats. (American journal of physiology. Gastrointestinal and liver physiology, 2026, PMID 41875058): "This study aimed to evaluate whether improvements of glucose homeostasis resulting from leptin administration can lead to changes in colonic epithelial metabolism and barrier function in male UC Davis type 2 diabetic mellitus (UCD-T2DM) rats."
May Cannabisin A and B from hemp seed hulls improve glucose homeostasis by re-engaging insulin, leptin, and AMPK pathways via selective PTP1B inhibition. (Phytomedicine : international journal of phytotherapy and phytopharmacology, 2026, PMID 41831381): "Protein-tyrosine phosphatase 1B (PTP1B) is a master negative regulator of insulin and leptin receptor tyrosine kinase (RTK) signaling, and its chronic overactivation is strongly implicated in metabolic dysfunction."