Leptin Resistance Research Peaks and Plateaus, Three-Decade Global Map Reveals

Few hormones have shaped obesity research as profoundly as leptin, the fat-derived signal that tells the brain how much energy the body carries. Now, a sweeping bibliometric analysis of more than three decades of scientific literature has mapped, for the first time, exactly how the global research community has pursued leptin resistance and its role in obesity-related metabolic dysfunction. The study, published in Health Science Reports, examined 2162 publications indexed in the Scopus database between 1995 and 2025, tracing who produced the field’s output, where it clustered, which journals carried it and how its intellectual vocabulary evolved from measuring blood leptin levels to dissecting hypothalamic inflammation and cardiometabolic risk.

The headline finding is a story of explosive growth followed by a plateau. Annual output rose from a single publication in 1995 to 91 in 2025, a compound annual growth rate of 16.2 percent, but the trajectory was anything but smooth. Research activity peaked in 2014 with 109 publications, fluctuated thereafter and settled into an average of 87.2 publications per year between 2015 and 2025, compared with just 37.3 annually during 1995 to 2004. Original articles dominated the corpus, accounting for 1658 publications or 76.69 percent, with reviews contributing another 433 papers, a proportion the author interprets as a sign that the field has accumulated enough evidence to require synthesis and clearer conceptual organisation.

Geographically, the field is strikingly concentrated. Affiliation strings resolved to 76 countries, yet the United States alone produced 741 publications, 34.27 percent of the corpus, and accumulated 83,759 citations, far ahead of any other nation. China ranked second with 255 publications, followed by Japan, Spain, Germany, Brazil, the United Kingdom, France, Australia and Canada. The collaboration network reinforced this picture of a hub-and-spoke world: the United States occupied the largest node and the strongest total link strength in the co-authorship map, maintaining collaborative ties with China, Japan, Canada, Germany, France, Spain, Australia, Italy and Brazil. Notably, the United Kingdom led the top ten in international collaboration, with 57.43 percent of its publications involving at least two countries, while American output was more domestically anchored at just under 30 percent.

Institutionally, the landscape is anchored by a handful of elite biomedical centres. After targeted harmonisation of affiliation variants, Harvard Medical School emerged as the most productive institution with 56 publications and the largest corpus-specific h-index of 43. Beth Israel Deaconess Medical Center, despite slightly fewer publications, recorded the highest total citations at 12,239 and an extraordinary 254.98 citations per publication, a figure that reflects its role in foundational leptin physiology work. INSERM, the Universidade de São Paulo, UT Southwestern Medical Center, the University of Iowa, CIBEROBN, the University of Michigan, the University of Washington and the University of Florida completed the top ten. At the author level, Brazilian researchers Lisboa P.C. and Moura E.G. led productivity with 33 and 31 papers respectively, while Kamal Rahmouni of the obesity-hypertension field posted the highest citation impact among prolific authors.

The journal analysis reveals a field that sprawls across disciplinary boundaries. Endocrinology published the most articles with 73, followed by Diabetes with 58 and the International Journal of Obesity with 47. PLOS One, the American Journal of Physiology titles, the International Journal of Molecular Sciences, Cell Metabolism, Molecular Metabolism and Frontiers in Endocrinology rounded out the top ten. Cell Metabolism boasted the highest citations per publication at 178.60, while Diabetes accumulated the greatest total citations at 9849. This dispersal, the study notes, mirrors the multidisciplinary nature of leptin resistance research itself, spanning endocrinology, neuroscience, molecular biology, physiology and cardiometabolic medicine.

The citation analysis doubles as a history of the field’s intellectual core. The most cited paper remains the 2001 Nature study by Cowley and colleagues demonstrating that leptin activates anorexigenic POMC neurons through a neural network in the arcuate nucleus, with 2052 citations. Close behind are Frederich and colleagues’ 1995 Nature Medicine paper providing evidence for diet-induced resistance to leptin action, with 1533 citations, and Kalra and colleagues’ 1999 Endocrine Reviews synthesis of hypothalamic appetite regulation, with 1457. Other heavily cited works include Caro and colleagues’ 1996 Lancet report of a decreased cerebrospinal-fluid-to-serum leptin ratio in obesity, Zabolotny and colleagues’ identification of PTP1B as a leptin signal regulator, Milanski and colleagues on hypothalamic TLR4 inflammation, and Ozcan and colleagues on endoplasmic reticulum stress as a driver of leptin resistance.

Beyond the central signalling story, the most-cited corpus stretches into the wider metabolic periphery. Highly cited papers on adipose tissue as an endocrine organ, gut microbiota responses in leptin-resistant mice, low-grade inflammation and type 2 diabetes, and obesity-associated hypertension show that leptin resistance has long been studied not as an isolated appetite defect but as a node in a broader cardiometabolic network. A year-normalised citation ratio in the analysis highlights how recent reviews, such as a 2021 Frontiers in Endocrinology overview of leptin’s clinical implications, have accumulated citations at an exceptional pace, with 947 citations and a normalised ratio of 24.90 against same-year peers.

The study’s visualisation component delivers perhaps its most quotable insight: the field’s vocabulary has visibly shifted. Using VOSviewer term co-occurrence mapping on titles and abstracts, with a threshold of 50 occurrences that admitted 257 of 28,255 terms, the analysis identified three thematic clusters. The first, clinical metabolic dysfunction and cardiometabolic risk, groups terms such as leptin level, insulin resistance, glucose, diabetes, metabolic syndrome, body mass index, inflammation, adiponectin, hypertension and cardiovascular disease. The second captures hypothalamic leptin signalling, appetite control and energy homeostasis, featuring hypothalamus, food intake, body weight, energy expenditure, neuropeptide, melanocortin, POMC neuron, arcuate nucleus, leptin receptor, diet-induced obesity and STAT3. The third links body weight regulation with developmental and experimental models, including rat, pregnancy, offspring, lactation and chow, pointing to a substantial literature on early-life nutritional programming of later metabolic dysfunction.

An overlay visualisation colouring each term by its average publication year makes the temporal evolution legible at a glance. Early blue-era terms include rat, serum leptin, leptin concentration, body mass index, neuropeptide and mRNA, the vocabulary of the field’s foundational decades. Intermediate green terms such as weight, diet, food intake, hypothalamus, mouse and insulin resistance mark the mechanistic middle period. The yellow frontier is dominated by inflammation, disease, diabetes, oxidative stress, pathogenesis, progression, risk, patient, hypertension, cardiovascular disease, adipokine, high-fat diet, molecular mechanism, glucose homeostasis and pathway. The author is careful to frame this as descriptive evidence of broadening vocabulary rather than proof of a causal transition, noting that lexical fashion and nomenclature changes, including the shift from NAFLD to MAFLD and MASLD, can shift average publication years independently of any genuine change in research focus.

The analysis also carries methodological rigour worth noting. The search strategy was validated by screening the 100 most-cited records for relevance, with irrelevant or partially related records below 5 percent, and by comparing retrieved output against the manually verified Scopus profiles of the top 20 most productive authors, achieving an intraclass correlation coefficient of 0.964. A boundary sensitivity rerun showed that including the broader expressions leptin sensitivity and leptin responsiveness added 281 publications, 13 percent of the corpus, all beyond the narrower query’s yield. Limitations are candidly acknowledged: reliance on a single database, citation counts that reflect age and visibility as much as quality, metadata disambiguation errors that may split or merge author identities, and an English-language search strategy that may miss relevant non-English work, even though the retrieved corpus included 164 non-English records. The paper closes by flagging the field’s most urgent gaps, including the absence of a widely accepted clinical definition of leptin resistance, the need to translate animal-model mechanisms into human metabolic outcomes, and the desirability of broader geographic participation in a literature still dominated by high-output nations.

Subject of Research: Bibliometric mapping of global research on leptin resistance and obesity-related metabolic dysfunction from 1995 to 2025

Article Title: Global Research Landscape on Leptin Resistance and Obesity‐Related Metabolic Dysfunction: Trends, Networks and Visualisation Analysis (1995–2025)

Article References: Zyoud, S. H. (2026). Global Research Landscape on Leptin Resistance and Obesity‐Related Metabolic Dysfunction: Trends, Networks and Visualisation Analysis (1995–2025). Endocrinology, Diabetes & Metabolism, 9(5), Article e70330. https://doi.org/10.1002/edm2.70330

Image Credits: AI Generated

DOI: 10.1002/edm2.70330

Keywords: leptin resistance, obesity, metabolic dysfunction, bibliometrics, hypothalamus, insulin resistance, inflammation, cardiometabolic risk, Scopus, VOSviewer, gut microbiota, type 2 diabetes