Obesity, metabolic health and omics: Current status and future directions

Table 1 Single nucleotide polymorphisms associated with metabolically healthy obese phenotype

Nearest gene	SNPs	Ref.
ADIPOQ	rs2241766	Berezina et al[31] and Chang et al[32]
MC4R	rs2331841	Gao et al[29]
LTF	rs2239692	Jamka et al[30]
FTO	rs1121980	Gharooi Ahangar et al[27]
TCF7L2	rs7903146	Gharooi Ahangar et al[27]
SLC39A8	rs13107325	Gharooi Ahangar et al[27]
RTP4	rs9028, rs9843429	Schlauch et al[26]
CDH18	rs1022207, rs2967027	Schlauch et al[26]
FST/LOC257396	rs37785, rs10461563	Schlauch et al[26]
FSTL4/WSPAR	rs7719102, rs4246020	Schlauch et al[26]
LOC107986637	rs11753543, rs9384860	Schlauch et al[26]
TRPS1	rs2245221, rs2737214, rs2737215	Schlauch et al[26]
DLG2	rs7131460, rs12275254	Schlauch et al[26]
TOX2	rs766622, rs6065690, rs6093921	Schlauch et al[26]
FAM19A2/SLC16A7	rs4143650, rs6581305	Schlauch et al[26]
LOC101927367/LOC105371833	rs11079177, rs12601773	Schlauch et al[26]
LOC105371989	rs206549, rs206547	Schlauch et al[26]
LOC107986666	rs9295227, rs9458896, rs6928576, rs6902153, rs10945918, rs7748991, rs9356148	Schlauch et al[26]

SNPs: Single nucleotide polymorphisms.

Table 2 Studies investigating genome-wide gene expression levels in metabolically healthy obese individuals

Biological material	Method	Study design	Sample size	Metabolic health definition	Main findings	Ref.
Whole blood	RNA-seq	MHO vs MUO	8/21	All conditions must be met: BP ≤ 130/85 mmHg, no medication; FPG ≤ 100 mg/dL, no medication; HOMA-IR ≤ 5.1; TG/HDL ≤ 1.65 for males, TG/HDL ≤ 1.32 for females; hsCRP ≤ 0.3 mg/dL	Enrichment in pathways: EIF2 signaling, eIF4 and p70S6K signaling, mTOR signaling. Enrichment in GO terms related to mRNA translation processes. Ribosomal protein genes among top differentially genes	Gaye et al[34]
Whole blood	RNA-seq	MHO vs MUO	8/8	No MetS, according to harmonized MetS definition	Enrichment in pathways: granulocyte/agranulocyte adhesion and diapedesis, coagulation system, intrinsic prothrombin activation pathway, atherosclerosis signaling, integrin signaling, binding and aggregation of blood cells	Paczkowska-Abdulsalam et al[35]
Whole blood	RNA-seq	MHO vs MHNW	8/8	No MetS, according to harmonized MetS definition	Enrichment in pathways: EIF2 signaling, eIF4 and p70S6K signaling, mTOR signaling, oxidative phosphorylation, mitochondrial dysfunction, vascular/arterial disease	Paczkowska-Abdulsalam et al[35]
PBMCs	Microarray	MHO vs MHNW	17/15	No MetS, according to NCEP ATP III MetS definition	Enrichment in pathways: carbohydrate metabolism, lipid metabolism, protein synthesis, amino acid metabolism, cell morphology, death and survival, cell-to-cell signaling and interaction, cellular development, movement, growth and proliferation	de Luis et al[36]
aSAT	Microarray	MHO vs MUO	16/14	MHO group identified through unsupervised hierarchical clustering of 1595 obesity-associated transcripts	Enrichment in pathways: complement system, TREM1 signaling, IL-8 signaling, actin cytoskeleton signaling, vascular disease, occlusion of artery	Das et al[37]

aSAT: Abdominal subcutaneous adipose tissue; PBMCs: Peripheral blood mononuclear cells; NCEP ATPIII: National Cholesterol Education Program Adult Treatment Panel III; BP: Blood pressure; FPG: Fasting plasma glucose; HOMA-IR: Homeostatic model assessment for insulin resistance; TG: Triglycerides; HDL: High-density lipoprotein; CRP: C-reactive protein; MHO: Metabolically healthy obese; IL: Interleukin.

Table 3 Different expression of micro-RNAs identified in metabolically healthy obese individuals

miRNA	Upregulation/ Downregulation	Sample size (MHO/MHNW)	Biological material	Ref.
MHO vs MHNW
hsa-miR-5001	↓	6/6	Plasma	Yang et al[47]
hsa-miR-4541	↓
hsa-miR-142	↓
hsa-miR-320a1	↓
hsa-miR-107	↓
hsa-miR-34a	↑
hsa-miR-211	↑
hsa-miR-99b	↑
hsa-miR-148a1	↑
hsa-miR-1261	↑
MHO vs MUO
hsa-miR-223-3p	↓	10/10	Serum	Doumatey et al[48]
hsa-miR-374a-5p1	↑
hsa-miR-10b-5p	↑
hsa-miR-26b-5p	↑
hsa-let-7d-3p	↑
hsa-miR-29a-3p	↑
hsa-miR-342-3p	↑
hsa-miR-16-2-3p	↑
hsa-miR-503	↑	34/21	Serum	Yue et al[49]

¹Validated with real-time reverse transcription polymerase chain reaction in an independent cohort. miRNA: Micro-RNAs; MHO: Metabolically healthy obese; MHNW: Metabolically healthy normal weight; MUO: Metabolically unhealthy obese.

Table 4 Proteins with altered expression in metabolically healthy obese compared to metabolically unhealthy obese individuals

Biological material	Over-expressed	Under-expressed	Top enriched pathways	Ref.
Serum	APOB, AHSG, SERPINC1, APOA4, SERPING1, RBP4, ITIH2, GSN, HRG, ITIH1, GC, C7	HBA1, HPR, HBB, CFB, ITIH4, CRP, PON1, C4A	LXR/RXR activation, FXR/RXR activation, acute phase response signaling, complement system, atherosclerosis signaling, IL-12 signaling and production in macrophages, production of nitric oxide and reactive oxygen species in macrophages, clathrin-mediated endocytosis signaling, extrinsic prothrombin activation pathway, intrinsic prothrombin activation pathway, coagulation system	Doumatey et al[58]
Urine	RASN, IGHG2, K1C10, VTDB	ACOT2, ARL15, APC4, APC7, APOA1, DYH3, FIBA, C1GLT, HIX, ITIH4, KNG1, P3H2, AMBP, COO33, RET4, TRFE, ZFP2, ZN568, ZN655	LXR/RXR activation, FXR/RXR activation, acute phase response signaling, clathrin-mediated endocytosis signaling, atherosclerosis signaling, IL-12 signaling and production in macrophages, coagulation system, intrinsic prothrombin activation pathway, production of nitric oxide and reactive oxygen species in macrophages, systemic lupus erythematosus signaling	Benabdelkamel et al[59]
VAT	ANXA5, ACTG, ACTB, LEG1, GPDA, APOA1, CO6A1, SBP1, CATA, TO20L, BRE1A, RNA58, SOX21	POTEE, SPTN4, GDIR1, TTHY, HSP1, PPIA, UPAR, PAI1, BLVRB, ERI2, YQ019	death receptor signaling, coagulation system, acute phase response signaling, RhoGDI signaling, NRF2-mediated oxidative stress response	Alfadda et al[60]

IL: Interleukin; VAT: Visceral adipose tissue; LXR: Liver X receptor; RXR: Retinoid X receptor, FXR: Farnesoid X receptor; NRF2: Nuclear factor erythroid 2-related factor 2; RhoGDI: Rho GDP-dissociation inhibitor.

Table 5 Differentially regulated pathways between metabolically healthy obese and metabolically unhealthy obese groups identified by metabolomics studies

Study	Chen et al[67], 2015	Zhong et al[68], 2017	Candi et al[71], 2018	Chashmniam et al[65], 2020
Biological material	Plasma	Plasma	VAT	Serum
Method	LC-MS, GC-MS	LC-MS/MS	LC-MS/MS	NMR
MHO definition	No MetS, according to NCEP ATP III MetS definition	No MetS, according to harmonized MetS definition	No MetS, according to NCEP ATP III MetS definition	No MetS, according to NCEP ATP III MetS definition
MHO (n)	34	43	18	21
MUO (n)	34	26	18	21
Affected pathways	Fatty acid biosynthesis; Phenylalanine metabolism; Propanoate metabolism; Valine, leucine and isoleucine degradation; Pyrimidine metabolism; Citrate cycle (TCA cycle); Galactose metabolism; Glyoxylate and dicarboxylate; and Tryptophan metabolism	Purine metabolism (i.e., urate); Valine, leucine and isoleucine degradation; Aminoacyl-tRNA biosynthesis; Tryptophan metabolism; Cysteine and methionine metabolism; Lysine degradation; Pyrimidine metabolism; Arginine and proline metabolism; Glycine, serine and threonine metabolism; Taurine and hypotaurine metabolism; Alanine, aspartate and glutamate metabolism; Pantothenate and CoA biosynthesis	Ceramide metabolism; Phosphatidylserine; Fatty acid, dicarboxylate; Glutathione metabolism; Lysoplasmalogen; Lysolipid; Aminosugar metabolism; Gamma-glutamyl amino acid; Pyrimidine metabolism, uracyl containing; Plasmalogen; Glycerolipid metabolism; Sphingolipid metabolism; Phopsholipid metabolism; Fructose, mannose, and galactose metabolism	Urea cycle; Ammonia recycling; Aspartate metabolism; Glycine and serine metabolism; Glucose-alanine cycle; and Arginine and proline metabolism

LC: Liquid chromatography; GC: Gas chromatography; MS: Mass spectrometry; NCEP ATP III: National Cholesterol Education Program Adult Treatment Panel III; TCA: Citric acid cycle; MetS: Metabolic syndrome; NMR: Nuclear magnetic resonance; MHO: Metabolically healthy obese; MUO: Metabolically unhealthy obese.