CoChat
Sign Up
Cited by 90Pharmacology and Obesity TreatmentAdipokines, Inflammation, and Metabolic DiseasesBerberine and alkaloids research

The DOI matches its Crossref record; 499 of the 499 references it cites were found in a registry or an index.

Obesity: pathophysiology and therapeutic interventions

Open access
Kong, Yue, Yang, Haokun, Nie, Rong, Zhang, Xuxiang, Zuo, Fan, Zhang, Hongtao, Nian, Xin·2025·Molecular Biomedicine
DOI 10.1186/s43556-025-00264-9PMC PMC12031720
Open this paper in CoChat — free accountOpen PDF

Abstract

Over the past few decades, obesity has transitioned from a localized health concern to a pressing global public health crisis affecting over 650 million adults globally, as documented by WHO epidemiological surveys. As a chronic metabolic disorder characterized by pathological adipose tissue expansion, chronic inflammation, and neuroendocrine dysregulation that disrupts systemic homeostasis and impairs physiological functions, obesity is rarely an isolated condition; rather, it is frequently complicated by severe comorbidities that collectively elevate mortality risks. Despite advances in nutritional science and public health initiatives, sustained weight management success rates and prevention in obesity remain limited, underscoring its recognition as a multifactorial disease influenced by genetic, environmental, and behavioral determinants. Notably, the escalating prevalence of obesity and its earlier onset in younger populations have intensified the urgency to develop novel therapeutic agents that simultaneously ensure efficacy and safety. This review aims to elucidate the pathophysiological mechanisms underlying obesity, analyze its major complications—including type 2 diabetes mellitus (T2DM), cardiovascular diseases (CVD), non-alcoholic fatty liver disease (NAFLD), obesity-related respiratory disorders, obesity-related nephropathy (ORN), musculoskeletal impairments, malignancies, and psychological comorbidities—and critically evaluate current anti-obesity strategies. Particular emphasis is placed on emerging pharmacological interventions, exemplified by plant-derived natural compounds such as berberine (BBR), with a focus on their molecular mechanisms, clinical efficacy, and therapeutic advantages. By integrating mechanistic insights with clinical evidence, this review seeks to provide innovative perspectives for developing safe, accessible, and effective obesity treatments.

Overview

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1186/s43556-025-00264-9

Cites

499 of 499 references verified0 citation errors · 0 not checkable

Statistics

Figures

Fig. 1 Energy Homeostasis and Metabolic Adaptation of Obesity. Obesity arises from disrupted energy homeostasis, characterized by excessive TG storage in WAT and impaired thermogenic capacity of BAT/BeAT. Mitochondrial dysfunction and suppressed WAT browning perpetuate metabolic inflexibility, driving IR and systemic metabolic disease. Interventions targeting adipose plasticity and mitochondrial health hold therapeutic potential. Figure 1 was created with BioGDP.com. AT, adipose tissue; WAT, white adipose tissue; BAT, brown adipose tissue; BeAT, beige adipose tissue; UCP1, uncoupling protein 1; FFA, free fatty acids; TG, triglycerides
Fig. 1 Energy Homeostasis and Metabolic Adaptation of Obesity. Obesity arises from disrupted energy homeostasis, characterized by excessive TG storage in WAT and impaired thermogenic capacity of BAT/BeAT. Mitochondrial dysfunction and suppressed WAT browning perpetuate metabolic inflexibility, driving IR and systemic metabolic disease. Interventions targeting adipose plasticity and mitochondrial health hold therapeutic potential. Figure 1 was created with BioGDP.com. AT, adipose tissue; WAT, white adipose tissue; BAT, brown adipose tissue; BeAT, beige adipose tissue; UCP1, uncoupling protein 1; FFA, free fatty acids; TG, triglyceridesCC BY · PubMed Central
Fig. 2 Hormonal Regulation Associated with Obesity. Obesity involves dysregulation of key hormones: Leptin resistance drives hyperphagia and energy imbalance. Insulin resistance promotes ectopic lipid accumulation and systemic metabolic dysfunction. Ghrelin suppression fails to counteract overeating. Adiponectin deficiency impairs lipid oxidation. GLP- 1 analogs offer therapeutic benefits by enhancing satiety. Ovarian hormones modulate hedonic and cognitive aspects of eating. Targeting leptin/insulin signaling, enhancing GLP- 1 activity, and restoring adiponectin levels may mitigate obesity-related metabolic disorders. Figure 2 was created with BioGDP.com. LepR, leptin receptor; POMC, pro-opiomelanocortin; ARC, arcuate nucleus; NPY, neuropeptide Y; NF-κB, nuclear factor-κB; IKKβ, NF-κB kinase-β; INSR, insulin receptor; AgRP/NPY, agouti-related peptide and neuropeptide Y; GHSR, growth hormone secretagogue receptor; SIRT1, sirtuin 1; CaMKK2, calcium/calmodulin-dependent protein kinase kinase 2; AMPK, AMP-activated protein kinase; ACO, acetyl CoA oxidase; UCPs, uncoupling proteins; GLP- 1, Glucagon-like peptide- 1; GLP- 1R, GLP- 1 receptor; Gαs, G protein α subunit; cAMP, cyclic AMP; PKA, protein kinase A; MAPK, mitogen-activated protein kinase; NTS, nucleus tractus solitarius
Fig. 2 Hormonal Regulation Associated with Obesity. Obesity involves dysregulation of key hormones: Leptin resistance drives hyperphagia and energy imbalance. Insulin resistance promotes ectopic lipid accumulation and systemic metabolic dysfunction. Ghrelin suppression fails to counteract overeating. Adiponectin deficiency impairs lipid oxidation. GLP- 1 analogs offer therapeutic benefits by enhancing satiety. Ovarian hormones modulate hedonic and cognitive aspects of eating. Targeting leptin/insulin signaling, enhancing GLP- 1 activity, and restoring adiponectin levels may mitigate obesity-related metabolic disorders. Figure 2 was created with BioGDP.com. LepR, leptin receptor; POMC, pro-opiomelanocortin; ARC, arcuate nucleus; NPY, neuropeptide Y; NF-κB, nuclear factor-κB; IKKβ, NF-κB kinase-β; INSR, insulin receptor; AgRP/NPY, agouti-related peptide and neuropeptide Y; GHSR, growth hormone secretagogue receptor; SIRT1, sirtuin 1; CaMKK2, calcium/calmodulin-dependent protein kinase kinase 2; AMPK, AMP-activated protein kinase; ACO, acetyl CoA oxidase; UCPs, uncoupling proteins; GLP- 1, Glucagon-like peptide- 1; GLP- 1R, GLP- 1 receptor; Gαs, G protein α subunit; cAMP, cyclic AMP; PKA, protein kinase A; MAPK, mitogen-activated protein kinase; NTS, nucleus tractus solitariusCC BY · PubMed Central
Fig. 3 The Neural Control of Obesity. The hypothalamic arcuate nucleus (ARC) regulates feeding behavior and energy homeostasis through two opposing neuronal populations: anorexigenic POMC neurons (reducing food intake via MC4R activation and increasing energy expenditure) and orexigenic NPY/AgRP neurons (promoting hunger and suppressing energy use). Chronic overnutrition (e.g., HFD, leptin deficiency) disrupts ARC plasticity, impairing homeostatic regulation through mechanisms like leptin signaling defects, ER stress, and metabolic inflammation. This inflammation alters neuropeptide secretion, desensitizes energy-balance neurons, and exacerbates dysregulation of appetite and metabolism. Figure 3 was created with BioGDP.com
Fig. 3 The Neural Control of Obesity. The hypothalamic arcuate nucleus (ARC) regulates feeding behavior and energy homeostasis through two opposing neuronal populations: anorexigenic POMC neurons (reducing food intake via MC4R activation and increasing energy expenditure) and orexigenic NPY/AgRP neurons (promoting hunger and suppressing energy use). Chronic overnutrition (e.g., HFD, leptin deficiency) disrupts ARC plasticity, impairing homeostatic regulation through mechanisms like leptin signaling defects, ER stress, and metabolic inflammation. This inflammation alters neuropeptide secretion, desensitizes energy-balance neurons, and exacerbates dysregulation of appetite and metabolism. Figure 3 was created with BioGDP.comCC BY · PubMed Central
Fig. 4 The Inflammation and Immune Responses of Obesity. Obesity induces AT inflammation via pro-inflammatory cytokines from dysfunctional adipocytes and immune cells, causing IR and systemic low-grade inflammation. Metabolic pathways like TLR4/PI3 K/Akt, ER stress, and NLRP3 inflammasome are involved. Immune dysregulation further exacerbates IR and chronic inflammation. Figure 4 was created with BioGDP.com. TLR4/PI3 K/Akt pathway, toll-like receptor 4/phosphatidylinositol- 3'- kinase/Protein kinase B pathway; NLRP3, nucleotide-binding and oligomerization domain (NOD) leucine-rich repeat family pyrin domain-containing 3; ATMs, adipose tissue macrophages; iNOS, inducible NO synthase; MCP- 1, monocyte chemoattractant protein- 1; cPLA2α, cytosolic phospholipase-A2α; ICAM- 1, endothelial cell adhesion molecule 1
Fig. 4 The Inflammation and Immune Responses of Obesity. Obesity induces AT inflammation via pro-inflammatory cytokines from dysfunctional adipocytes and immune cells, causing IR and systemic low-grade inflammation. Metabolic pathways like TLR4/PI3 K/Akt, ER stress, and NLRP3 inflammasome are involved. Immune dysregulation further exacerbates IR and chronic inflammation. Figure 4 was created with BioGDP.com. TLR4/PI3 K/Akt pathway, toll-like receptor 4/phosphatidylinositol- 3'- kinase/Protein kinase B pathway; NLRP3, nucleotide-binding and oligomerization domain (NOD) leucine-rich repeat family pyrin domain-containing 3; ATMs, adipose tissue macrophages; iNOS, inducible NO synthase; MCP- 1, monocyte chemoattractant protein- 1; cPLA2α, cytosolic phospholipase-A2α; ICAM- 1, endothelial cell adhesion molecule 1CC BY · PubMed Central
Fig. 5 Genetic and Epigenetic Mechanisms of Obesity. Genetic and epigenetic mechanisms critically shape obesity susceptibility. Maternal obesity, particularly in obesogenic or hyper-nutritional environments during pregnancy, induces metabolic dysregulation characterized by placental exposure to inflammation, oxidative stress, lipid accumulation, insulin resistance, and gut microbiota alterations. These pathological conditions drive epigenetic modifications and genetic mutations, thereby predisposing offspring to childhood obesity. This mechanistic cascade underscores the necessity of early clinical screening to identify at-risk populations and implement targeted preventive or therapeutic interventions. Figure 5 was created with BioGDP.com. MC4R, melanocortin 4 receptor; IR, insulin resistance
Fig. 5 Genetic and Epigenetic Mechanisms of Obesity. Genetic and epigenetic mechanisms critically shape obesity susceptibility. Maternal obesity, particularly in obesogenic or hyper-nutritional environments during pregnancy, induces metabolic dysregulation characterized by placental exposure to inflammation, oxidative stress, lipid accumulation, insulin resistance, and gut microbiota alterations. These pathological conditions drive epigenetic modifications and genetic mutations, thereby predisposing offspring to childhood obesity. This mechanistic cascade underscores the necessity of early clinical screening to identify at-risk populations and implement targeted preventive or therapeutic interventions. Figure 5 was created with BioGDP.com. MC4R, melanocortin 4 receptor; IR, insulin resistanceCC BY · PubMed Central
Fig. 6 The Gut Microbiota Dysbiosis of Obesity. Gut microbiota dysbiosis contributes to obesity via multiple mechanisms: altered microbial composition, circadian disruption, SCFA-mediated lipogenesis, pathogenic strain activity, and compromised intestinal barrier integrity. Therapeutic strategies targeting microbial balance, barrier restoration, or specific taxa may mitigate obesity-related metabolic disorders. Figure 6 was created with BioGDP.com. HFD, high fat diet; LPS, lipopolysaccaride; SCFAs, Short-Chain Fatty Acids; CHREBP, carbohydrate responsive element-binding protein; SREBP1, sterol regulatory element-binding transcription factor- 1
Fig. 6 The Gut Microbiota Dysbiosis of Obesity. Gut microbiota dysbiosis contributes to obesity via multiple mechanisms: altered microbial composition, circadian disruption, SCFA-mediated lipogenesis, pathogenic strain activity, and compromised intestinal barrier integrity. Therapeutic strategies targeting microbial balance, barrier restoration, or specific taxa may mitigate obesity-related metabolic disorders. Figure 6 was created with BioGDP.com. HFD, high fat diet; LPS, lipopolysaccaride; SCFAs, Short-Chain Fatty Acids; CHREBP, carbohydrate responsive element-binding protein; SREBP1, sterol regulatory element-binding transcription factor- 1CC BY · PubMed Central
Fig. 7 The Complications of Obesity. The complications of obesity mainly include T2DM, CVD, NAFLD, respiratory disorders, ORN, musculoskeletal disorders, cancers, psychological comorbidities and others. Figure 7 was created with BioGDP.com. T2DM, type 2 diabetes mellitus; CVD, cardiovascular diseases; NAFLD, non-alcoholic fatty liver disease; ORN, obesity-related nephropathy; APCs, adipocyte precursor cells; LDL, Low Density Lipoprotein; CAD, coronary artery disease; SCD, sudden cardiac death; MASH, metabolic dysfunction-associated steatohepatitis; HCC, hepatocellular carcinoma; OSA, obstructive sleep apnea; VEGF-B, vascular endothelial growth factor-B; ROS, reactive oxygen species; ER, endoplasmic reticulum; VD, Vitamin D; MM, multiple myeloma; Ca, cancer; POCS, polycystic ovary syndrome; TMJ OA, Temporomandibular joint osteoarthritis; AP, acute pancreatitis
Fig. 7 The Complications of Obesity. The complications of obesity mainly include T2DM, CVD, NAFLD, respiratory disorders, ORN, musculoskeletal disorders, cancers, psychological comorbidities and others. Figure 7 was created with BioGDP.com. T2DM, type 2 diabetes mellitus; CVD, cardiovascular diseases; NAFLD, non-alcoholic fatty liver disease; ORN, obesity-related nephropathy; APCs, adipocyte precursor cells; LDL, Low Density Lipoprotein; CAD, coronary artery disease; SCD, sudden cardiac death; MASH, metabolic dysfunction-associated steatohepatitis; HCC, hepatocellular carcinoma; OSA, obstructive sleep apnea; VEGF-B, vascular endothelial growth factor-B; ROS, reactive oxygen species; ER, endoplasmic reticulum; VD, Vitamin D; MM, multiple myeloma; Ca, cancer; POCS, polycystic ovary syndrome; TMJ OA, Temporomandibular joint osteoarthritis; AP, acute pancreatitisCC BY · PubMed Central
Fig. 8 The Interventions of Obesity. The primarily treatment interventions for obesity are summarized, which principally include lifestyle intervention, pharmacotherapy, bariatric surgery, and emerging therapies. Figure 8 was created with BioGDP.com. ER, extended release; SR, sustained release; SG, Sleeve gastrectomy; RYGB, Roux-en-Y gastric bypass; AGB, adjustable gastric banding; BPD-DS, biliopancreatic diversion with duodenal switch; OAGB, One anastomosis gastric bypass; SADI-S, single-anastomosis duodenal ileostomy with sleeve gastrectomy; BBR, Berberine; 11β-HSD1, 11β-hydroxysteroid dehydrogenase type 1; FO, fish oil; PCP, Penthorum chinense Pursh; MD- 2, Myeloid differentiation factor 2; DSG, Diosgenin; PL, pancreatic lipases
Fig. 8 The Interventions of Obesity. The primarily treatment interventions for obesity are summarized, which principally include lifestyle intervention, pharmacotherapy, bariatric surgery, and emerging therapies. Figure 8 was created with BioGDP.com. ER, extended release; SR, sustained release; SG, Sleeve gastrectomy; RYGB, Roux-en-Y gastric bypass; AGB, adjustable gastric banding; BPD-DS, biliopancreatic diversion with duodenal switch; OAGB, One anastomosis gastric bypass; SADI-S, single-anastomosis duodenal ileostomy with sleeve gastrectomy; BBR, Berberine; 11β-HSD1, 11β-hydroxysteroid dehydrogenase type 1; FO, fish oil; PCP, Penthorum chinense Pursh; MD- 2, Myeloid differentiation factor 2; DSG, Diosgenin; PL, pancreatic lipasesCC BY · PubMed Central
Fig. 9 The Mainly Anti-Obesity Mechanisms of BBR. BBR exerts anti-obesity effects through multiple mechanisms: 1) Suppressing adipocyte differentiation by downregulating C/EBP-α, PPAR-γ, and CREB; 2) Promoting browning of WAT via activation of BAT marker genes (e.g., PGC- 1α, UCP1) and mitochondrial biogenesis; 3) Regulating lipid metabolism by upregulating LDLR and Ampk-SIRT1-PPAR-γ pathway; 4) Modulating gut microbiota by increasing Bacteroidetes/Firmicutes ratio and SCFA-producing bacteria; 5) Polarizing adipose tissue macrophages from M1 to M2 phenotype to reduce inflammation; 6) Inhibiting inflammatory pathways (e.g., NF-κB, PI3 K/AKT/mTOR) and cytokines (e.g., TNF-α, IL- 6). Figure 9 was created with BioGDP.com. C/EBP-α, CCAAT/enhancer-binding protein-α; PPAR-γ, peroxisome proliferator-activated receptor γ; CREB, cAMP-response element-binding protein; Gal- 3, Galectin- 3; α-KG, α-ketoglutarate; LDLR, low density lipoprotein receptor; RhoA, Ras homolog gene family member A; NRF2, nuclear factor erythroid 2; SLC7 A11, recombinant solute carrier family 7 member 11; GPX4, glutathione peroxidase 4; GM, gastrointestinal microbiota; ATMs, adipose tissue macrophages. Remarks: All above figures were created with BioGDP.com
Fig. 9 The Mainly Anti-Obesity Mechanisms of BBR. BBR exerts anti-obesity effects through multiple mechanisms: 1) Suppressing adipocyte differentiation by downregulating C/EBP-α, PPAR-γ, and CREB; 2) Promoting browning of WAT via activation of BAT marker genes (e.g., PGC- 1α, UCP1) and mitochondrial biogenesis; 3) Regulating lipid metabolism by upregulating LDLR and Ampk-SIRT1-PPAR-γ pathway; 4) Modulating gut microbiota by increasing Bacteroidetes/Firmicutes ratio and SCFA-producing bacteria; 5) Polarizing adipose tissue macrophages from M1 to M2 phenotype to reduce inflammation; 6) Inhibiting inflammatory pathways (e.g., NF-κB, PI3 K/AKT/mTOR) and cytokines (e.g., TNF-α, IL- 6). Figure 9 was created with BioGDP.com. C/EBP-α, CCAAT/enhancer-binding protein-α; PPAR-γ, peroxisome proliferator-activated receptor γ; CREB, cAMP-response element-binding protein; Gal- 3, Galectin- 3; α-KG, α-ketoglutarate; LDLR, low density lipoprotein receptor; RhoA, Ras homolog gene family member A; NRF2, nuclear factor erythroid 2; SLC7 A11, recombinant solute carrier family 7 member 11; GPX4, glutathione peroxidase 4; GM, gastrointestinal microbiota; ATMs, adipose tissue macrophages. Remarks: All above figures were created with BioGDP.comCC BY · PubMed Central

Verification

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Citations

Cites

Items 201–400 of 499

Cited by

Sorted by citations

See all 90

Related

See all

Metadata

Authors
Kong, Y., Yang, H., Nie, R., Zhang, X., Zuo, F., Zhang, H., & Nian, X.
Affiliations
  • First Affiliated Hospital of Kunming Medical University (CN)
  • Kunming Medical University (CN)
Corresponding author
  • Zhang, Hongtao
  • Nian, Xin
ORCID
Venue
Molecular Biomedicine
Publisher
Springer Science and Business Media LLC
Published
2025-04-25
Volume
6
Issue
1
Pages
25-25
ISSN
2662-8651 (ISSN-L)
DOI
10.1186/s43556-025-00264-9
PMC
PMC12031720
OpenAlex
W4409818142
Cited by
89
References
499
Citations by year
2026: 77 · 2025: 12
FWCI
12.08
Type
journal article
Language
en
Open access
Licence
Locations
  • Molecular Biomedicine (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • Kunming Medical University (RLMY20220005, CXTD202209, 202201AY070001-066)
  • Yunnan Provincial Science and Technology Department (202201AY070001)
Topics
  • Health Sciences › Medicine › Pharmacology (medical) › Pharmacology and Obesity Treatment
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adipokines, Inflammation, and Metabolic Diseases
  • Health Sciences › Medicine › Pharmacology (medical) › Berberine and alkaloids research
Keywords
obesity, obesity pathophysiology, adipose tissue expansion, chronic inflammation, neuroendocrine dysfunction, obesity-related comorbidities, type 2 diabetes, cardiovascular disease, non-alcoholic fatty liver disease, musculoskeletal impairment, psychological comorbidity, obesity pharmacotherapy, berberine, phytochemicals, weight management
MeSH terms
Animals, Cardiovascular Diseases, Diabetes Mellitus, Type 2, Humans, Obesity, Anti-Obesity Agents, Non-alcoholic Fatty Liver Disease

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review