Metabolomic Signature Between Metabolically Healthy Overweight/Obese and Metabolically Unhealthy Overweight/Obese: A Systematic Review

Figures & data

Figure 1 PRISMA flow diagram of this systematic review.

Note: Adapted from Moher D, Liberati A, Tetzlaff J, Altman DG, The PRISMA Group (2009). Preferred Reporting Items for Systematic Reviews and Meta-Analyses: The PRISMA Statement. PLoS Med 6(7): e1000097.

Table 1 Characteristics of Studies Identifying Metabolomic Signature Compared Between Metabolically Unhealthy Overweight/Obese and Metabolically Healthy Overweight/Obese

Study (Year)	Country	Study Design	Population (Tissue)	Platform	Criteria for Definition of Metabolic Health	BMI Categories	Sample Size (n)	Mean Age	Male (%)	BMI (kg/m^2)	Score
1. Telle-Hansen et.al (2020)^Citation20	Norway	Cross-sectional study	Adult (plasma)	GC-MS; GC-FID; NMR (targeted)	≥3 of the following criteria: HOMA-IR index ≤ 1.95, TG ≤ 1.7 mmol/L, TC ≤ 5.2 mmol/L, LDL-cholesterol ≤ 2.6 mmol/L, and HDL-cholesterol ≥ 1.3 mmol/L.	Normal weight BMI ≤ 25 kg/m^2; obese BMI ≥ 30 kg/m^2	MHO (9)	49 (42–63)	5 (55)	33 (30–37)	10
							MUO (10)	52 (43–59)	9 (90)	32 (30–34)
2. Kim et.al (2020)^Citation21	Korea	Case-control study	Adult (plasma)	LC-MS (untargeted)	Metabolic syndrome: SBP ≥ 130 mmHg or DBP ≥ 85 mmHg, TG ≥ 150 mg/dL, TC ≥ 200 mg/dL, HDL cholesterol < 40 mg/dL in males or < 50 mg/dL in females, LDL cholesterol ≥ 130 mg/dL, fasting glucose ≥ 100 mg/dL, and visceral fat area at L4 ≥ 100 cm^2. Metabolically health have normal status in all of the above indices, except in the waist circumference.	Obese 25 kg/m^2 ≤ BMI < 30 kg/m^2	MHO (34)	35.7 ± 1.62	6 (17.6)	27.0 ± 0.20	12
							MUO (34)	37.3 ± 1.41	6 (17.6)	27.1 ± 0.22
3. Chashmniam et.al (2020)^Citation22	Iran	Case-control study	Adult (serum)	^1H-NMR (untargeted)	Meeting all the following criteria: SBP < 140 mmHg and DBP<90 mmHg, no antihypertensive drug use, FBS < 126 mg/dl, no hypoglycemic agents use, and serum levels of HDL cholesterol ≥ 40 mg/dL in men or ≥ 50 mg/dL in women.	Non-obese BMI < 30 kg/m^2; obese BMI ≥ 30 kg/m^2	MHO (21)	29 (25.0–35.0)	8 (38.1)	31.7 (30.45–32.60)	13
							MUO (21)	26 (23–33)	10 (47.6)	31.2 (30.5–33.3)
4. Ojwang et.al (2019)^Citation23	South Africa	Cross-sectional study	Adult (plasma)	GC-MS/MS (targeted)	Metabolic syndrome (JIS recommendations) ≥ 3 criteria: FPG levels ≥ 5.6 mmol/l or the use of oral hypoglycaemic medication, serum TG ≥ 1.7 mmol/l, serum HDL ≤ 1.0 mmol/l for men and ≤ 1.3 mmol/l for women, BP ≥ 130/85 mmHg or the use of BP medication, and WC of ≥ 94 cm for men and ≥ 80 cm for women. Metabolically health was defined as without metabolic syndrome.	Underweight and healthy weight BMI < 25 kg/m^2; overweight and obesity BMI ≥ 25 kg/m^2	MHO^a (120)	49 (43–56)	Unclear	30.4 (26.9, 34.1)	9
							MUO^a (167)	55 (48–65)	Unclear	31 (27.6, 34.5)
5 Rousseau et.al (2019)^Citation37	Canada	Cross-sectional study	Adult (plasma)	MS (targeted)	Metabolic syndrome: ≥3 of the following criteria: WC > 88 cm for women and 102 cm for men, fasting plasma TG ≥ 1.7 mmol/L, HDL-cholesterol levels ≤ 1.29 mmol/L for women and 1.03 mmol/L for men, glucose levels ≥ 5.6 mmol/L and resting SBP/DBP ≥ 130/85 mmHg. Metabolically health was defined as without metabolic syndrome.	Normal weight BMI < 25kg/m^2; overweght BMI > 25kg/m^2	MHO^a (84)	35.7 ± 10.4	41(48.9)	31.4 ± 4.2	10
							MUO^a (48)	38.4± 10.1	31(64.6)	34.3 ± 4.8
6. Libert et.al (2018)^Citation13	USA	Case-control study	Adult (plasma)	HPLC-UV; LC-MS/MS (targeted)	Metabolic syndrome: ≤1 of the ATP III criteria: BP ≥ 130/≥ 85 mmHg, fasting glucose ≥ 110 mg/dL, HDL < 40 mg/dL for men, < 50 mg/dL for women, TG ≥ 150 mg/dL, and WC > 40 in. for men, > 35 in. for women	Normal weight BMI < 25 kg/m^2; obese BMI > 30 kg/m^2	MHO (26)	37.5 ±10.5	12 (46)	35.0 (33.0, 39.7)	10
							MUO (20)	38.7 ± 11.7	11 (55)	37.4 (32.6, 40.0)
7. Candi et.al (2018)^Citation24	Italy	Case-control study	Adult (visceral adipose tissue)	GC/MS;LC/MS/MS (untargeted)	Metabolic syndrome: ≥ 3 of the ATP III criteria: WC > 40 inches (men) or 35 inches (women), BP > 130/85 mmHg, fasting TG level > 150 mg/dl, fasting HDL cholesterol < 40 mg/dl (men) or 50 mg/dl (women) and fasting blood sugar > 100 mg/dl. Metabolically health was defined as without metabolic syndrome.	Obese BMI > 40 kg/m^2	MHO (18)	Unclear	4 (22.2)	43.16 ± 1.57	11
							MUO (18)	Unclear	8 (44.4)	48.59 ± 1.72
8. Bervoets et.al (2018)^Citation25	Belgium	Case-control study	Children and adolescent (plasma)	^1H NMR (untargeted)	Metabolic syndrome: ≥ 2 of the International Diabetes Federation (IDF) criteria: HDL- cholesterol < 40mg/dl (females 16 years or older: HDL- cholesterol < 50 mg/dl), TG ≥ 150 mg/dl, SBP ≥ 130 mm Hg or DBP ≥ 85 mm Hg, fasting plasma glucose ≥ 100 mg/dl. Metabolically health was defined as without metabolic syndrome.	Normal-weight, overweight or obese according to IOTF BMI criteria	MHO^a (18)	13.4 ± 2.0	10 (55.6)	31.4 (23.6–36.0)	12
							MUO^a (17)	13.2 ± 2.0	10 (58.8)	33.4 (27.3–44.1)
9. Bagheri et.al (2018)^Citation26	Iran	Case-control study	Adult (plasma)	LC-MS(targeted)	≤1 of the IDF criteria, except the WC: Hypertension (characterized as SBP ≥ 130 mmHg or DBP ≥ 85 mmHg or a history of taking anti-hypertensive medication), impaired FBS ≥ 100 mg/dL and < 126 mg/dL, TG ≥ 150 mg/dL and HDL-cholesterol < 40 mg/dL in men or < 50 mg/dL in women.	Normal weight 18.5 kg/m^2 ≤ BMI < 25 kg/m^2; obese BMI ≥ 30 kg/m^2	MHO (107)	35.0 (30.5–41.5)	39.0 (36.0)	33.9 (31.8–36.4)	12
							MUO (100)	36.0 (31.8–43.0)	49.0 (49.0)	35.0 (32.8–38.4)
10. Zhong et.al (2017)^Citation27	USA	Case-control study	Adult (Plasma)	HPLC-MS/MS (targeted)	Metabolic syndrome: ≥3 of the following criteria: WC ≥ 102 cm for men and ≥ 88 cm for women, fasting TG ≥ 150 mg/dL, fasting glucose ≥ 100 mg/dL, resting systolic ≥ 130 mmHg and diastolic ≥ 85 mmHg blood pressure, and HDL-cholesterol < 40 mg/dL for men and < 50 mg/dL for women. Metabolically health was defined as without metabolic syndrome.	Obese BMI ≥ 30kg/m^2	MHO (43)	29.3 ± 10.3	12 (27.9)	35.2 ± 6.8	12
							MUO (26)	27.4 ± 9.8	17 (65.4)	35.2 ± 6.8
11. Allam-Ndoul et.al (2016)^Citation29	Canada	Case-control study	Adult (plasma)	MS (targeted)	Metabolic syndrome: ≥3 of the following criteria: WC > 88 cm for women and 102 cm for men, fasting plasma TG ≥ 1.7 mmol/L, HDL- cholesterol levels ≤ 1.03 mmol/L for men and 1.29 mmol/L for women, glucose levels ≥ 5.6 mmol/L and resting blood pressure ≥ 130/85 mmHg. Metabolically health was defined as without metabolic syndrome.	Overweight and obese BMI ≥ 25 kg/m^2; obese Body fat ≥ 25% of total body fat mass in men and ≥ 30% in women	MHO^a (83)	35.7 ± 10.4	Unclear	31.4 ± 4.2	8
							MUO^a (46)	37.9 ± 10.0	Unclear	34.3 ± 4.9
12. Gao et.al (2016)^Citation28	Canada	Case-control study	Adult (Serum)	LC-MS/MS (targeted)	HOMA-IR < 4.27, HDL-cholesterol level ≥ 1.03 mmol/L in men and ≥ 1.30 mmol/L in women, fasting blood glucose < 5.6 mmol/L, and WC ≤ 102 cm in men and ≤ 88 cm in women.	Normal weight 18 kg/m^2 < BMI < 25 kg/m^2; obese BMI ≥ 27.2 kg/m^2	MHO (30)	43.4 ± 11.8	15 (50)	30.1 ± 1.4	11
							MUO (29)	49.3 ± 11.4	14 (48.3)	31.6 ± 3.2
13. Ni et.al (2015)^Citation30	China	Cross-sectional study	Adult (serum)	UPLC-QTOF-MS (targeted)	Meeting all the following criteria: FPG ≤ 6.1 mmol/L, OGTT ≤ 7.8 mmol/L and no previous history of diabetes, SBP/DBP < 140/90 mmHg and no previous history of high blood pressure, fasting plasma TG < 1.7 mmol/L and fasting plasma HDL ≥ 0.9 mmol/L (men) or ≥ 1.0 mmol/L (women), and no previous history of high cholesterol (TC < 5.18mmol/L), no cardiovascular or endocrine disease history.	Normal weight < 24 kg/m^2; overweight ≥ 24 kg/m^2; obesity ≥28 kg/m^2	MHO^a (107)	46.269 ± 0.788	39 (36.5)	27.11 ± 0.18	10
							MUO^a (73)	57.111 ± 0.846	37 (50.7)	27.68 ± 0.3
14. Chen et.al (2015)^Citation31	China (Taiwan)	Case-control study	Adult (plasma)	LC-MS; GC-MS (targeted and untargeted)	Metabolic syndrome (ATP III criteria for Asian): fasting blood glucose > 100 mg/dL, TG > 150 mg/dL, HDL cholesterol < 40 mg/dL in males or 50 mg/dL in females, SBP > 130mmHg or DBP > 85mmHg. Metabolically health was defined as having normal status in all of the above indexes, except in the WC.	Obese BMI > 25 kg/m^2	MHO (34)	32.12 ± 7.92	17 (50)	31.53 ± 6.03	11
							MUO (34)	34.68 ± 8.73	17 (50)	34.16 ± 6.92
15. Böhm et.al (2014)^Citation34	Germany	Case-control study	Adult (culture of human adipocytes; plasma)	GC-MS; LC-MS/MS; HILIC-ESI-MS/MS (targeted)	Based on insulin sensitivity index, metabolically health was defined as insulin-sensitive.	Obese BMI > 40 kg/m^2	MHO (10)	45 ± 9	4 (40)	52.5 ± 8.9	11
							MUO (10)	38 ± 13	4 (40)	51.1 ± 6.9
16. Badoud et.al (2014)^Citation35	Canada	Case-control study	Adult (serum)	GC-MS; CE-MS (targeted and untargeted)	≥3 of the following criteria: HDL-cholesterol > 1.0 mmol/L for males and > 1.3 mmol/L for females, TG < 1.7 mmol/L without use of lipid-lowering drugs, TC < 5.2 mmol/L; LDL cholesterol < 2.6 mmol/L, and HOMA-IR < 1.95 without use of antidiabetic drugs.	Normal weight BMI < 28 kg/m^2 for males and <24 kg/m^2 for females; obese ≥ 28 kg/m^2 for males and ≥ 24 kg/m^2 for females	MHO (10)	50 ± 4	3 (30)	30.6 ± 1.1	13
							MUO (10)	48 ± 2	3 (30)	33.0 ± 1.9
17. Perreault et.al (2014)^Citation32	Canada	Case-control study	Adult (serum)	GC (targeted)	≥3 of the following criteria: HDL- cholesterol >1.0 mmol/L for males and > 1.3 mmol/L for females, TG < 1.7 mmol/L without use of lipid-lowering drugs, TC < 5.2 mmol/L, LDL-cholesterol < 2.6 mmol/L, and HOMA-IR < 1.95 without use of anti-diabetic drugs	Normal weight BMI < 28 kg/m^2 for males and < 24 kg/m^2 for females, obese BMI ≥ 28 kg/m^2 for males and < 24 kg/m^2 for females	MHO (10)	50 ± 4	3 (30)	30.6 ± 1.1	11
							MUO (10)	48 ± 2	3 (30)	33.0 ± 1.9
18. Wiklund et.al (2014)^Citation33	Finland	Cross-sectional study	Adult (serum)	NMR (targeted)	Metabolic syndrome: ≥ 3 of the following criteria: WC ≥ 88 cm, fasting serum TG ≥ 1.7 mmol/L, HDL-cholesterol < 1.30 mmol/L, glucose ≥ 5.6 mmol/L and resting blood pressure ≥ 130/85 mmHg. Metabolically health was defined as having normal status in all of the above indexes, except in the WC.	BMI between 25 and 40 kg/m^2	MHO^a (42)	39.7 ± 7.6	0	28.9 ± 3.2	12
							MUO^a (36)	44.1 ± 6.1	0	30.6 ± 3.4
19. Batch et.al (2013)^Citation36	USA	Cross-sectional study	Adult (plasma)	MS/MS (targeted)	≤1 of Cardiometabolic abnormalities: impaired fasting glucose ≥ 100 mg/dL and ≤ 126 mg/dL, hypertension (defined as a self-reported diagnosis of hypertension or taking a blood pressure medication), TG ≥ 150 mg/dL, HDL-cholesterol < 40 mg/dL in men or < 50 mg/dL in women, and HOMA-IR > 5.13.	Normal weight BMI < 25 kg/m^2, overweight 25kg/m^2 ≤ BMI < 30 kg/m^2, obese BMI ≥ 30 kg/m^2	MHO (114)	55.84 ± 11.45	39 (34)	34.63 ± 4.14	10
							MUO (738)	57.14 ± 10.72	384 (52)	36 ± 4.96
20. Ni et.al (2015)^Citation30	China	Cohort study	Adult (serum)	UPLC-QTOF-MS (targeted)	Meeting all the following criteria: FPG ≤ 6.1 mmol/L, OGTT ≤ 7.8 mmol/L and no previous history of diabetes, SBP/DBP <140/90 mmHg and no previous history of high blood pressure, fasting plasma TG < 1.7 mmol/L and fasting plasma HDL ≥ 0.9 mmol/L (men) or ≥ 1.0 mmol/L (women), and no previous history of high cholesterol (TC < 5.18mmol/L), no cardiovascular or endocrine disease history.	Normal weight < 24 kg/m^2; overweight ≥ 24 kg/m^2; obesity ≥ 28 kg/m^2	MHO^a (12)	39.92 ± 3.66	1 (8.3)	26.88 ± 0.47	10
							MUO^a (50)	43.94 ± 1.83	15 (30)	26.89 ± 0.37

Notes: ^aInclude overweight and obese, not marked with ^ainclude only obese.

Abbreviations: MUO, metabolically unhealthy overweight/obese; MHO, metabolically healthy overweight/obese; HOMA-IR, homeostasis model assessment of insulin resistance; TG, triglyceride; TC, total cholesterol; LDL, low-density lipoprotein; HDL, high density lipoprotein; SBP, systolic blood pressure; DBP, diastolic blood pressure; FBS, fasting blood sugar; FPG, fasting plasma glucose; BP, blood pressure; WC, waist circumference; OGTT, oral glucose tolerance test.

Table 2 Significant Findings Compared Between Metabolically Unhealthy Overweight/Obese and Metabolically Healthy Overweight/Obese

Study (Year)	Significant Findings
1.Telle-Hanse et.al (2020)^Citation20	Apolipoproteins: ApoB (↑), ApoA-I (↓), ApoB/ApoA-I (↑) Cholesterol: Remnaut-C (↑), VLDL-C (↑), HDL-C (↓), HDL2-C (↓) Triglycerides: TG (↑), VLDL-TG (↑), LDL-TG (↑), HDL-TG (↑) Phospholipids: TG-PG ratio (↑) Amino acids, branched-chain: Isoleucine (↑), Leucine (↑), Valine (↑) Short-chain FA: Propionate (↓) SFA: C16:0 (↑), C20:0 (↓), C22:0 (↓), C23:0 (↓) MUFA: MUFA (↑), C16:1 (↑), C18:1 c9 (↑), C18:1 c11 (↑) PUFA, total and n6: PUFA (↓), C18:2 n6 (↓) PUFA, n3: C22:5 n3 (↓) Ratio: 16:1/16:0 ratio (↑), 18:1/18:0 ratio (↑)
2. Kim et.al (2020)^Citation21	Glycolic acid (↓) lysoPEs (↑): 16:0, 18:2, 18:1, 20:5, 20:4, 22:6 lysoPCs (↑): 14:0, 16:1, 16:0, 18:4, 18:3, 18:2, 18:1, 20:5, 20:4, 20:3, 22:6, 22:5
3. Chashmniam et.al (2020)^Citation22	Alanine (↓), Glutamine (↓), Proline (↓), Asparagine (↓), L-Glutathione reduced (↓), Betaine (↓), Taurine (↓), Choline (↓), 2-Aminobutyrate (↓), Tagatose (↓), 2-Oxoglutarate (↓), L-alpha-phosphatidylinositol (↑), D-Sphingosine (↑)
4. Ojwang et.al (2019)^Citation23	Plasma phospholipid fatty acids: Saturated: C16:0 (↑), C18:0 (↓), C20:0 (↓), C22:0 (↓), C24:0 (↓) Monounsaturated: C16:1 n7 (↑), C18:1 n9 (↑), C20:1 n9 (↓), C22:1 n9 (↓), C24:1 n9 (↓) PUFA, n3: C20:5 n3 (↑) PUFA, n6: C18:3 n6 (↑), C20:2 n6 (↓), C22:2 n6 (↓), Total n-6 (↓) Trans-fatty acid: C18:1 n9T (↓)
5. Rousseau et.al (2019)^Citation37	BCAAs (↑): Valine, Leucine and Isoleucine Acylcarnitines (↑): C3, C5
6. Libert et.al (2018)^Citation13	Alanine (↑), Alloisoleucine (↑), Alpha-aminoadipic acid (↑), Cystine (↑), Isoleucine (↑), Leucine (↑), Lysine (↑), Phenylalanine (↑), Propionylcarnitine (↑), Tyrosine (↑), Valine (↑) Essential AAs (↑) (Histidine+ Isoleucine+ Leucine+ Lysine+ Methionine+ Phenylalanine+ Threonine+ Tryptophan+ Valine) Ketogenic AAs (↑) (Leucine+Lysine) Determines brain serotonin synthesis (↓): Tryptophan/(Tyrosine +Phenylalanine +Leucine +Isoleucine +Valine) BCAA metabolism (↑): (C3+C5)/Total carnitine
7.Candi et.al (2018)^Citation24	Glutathione Metabolism: glutathione, oxidized (GSSG) (↑), 5-oxoproline (↑), 2-hydroxybutyrate/2-hydroxyisobutyrate (↑), ophthalmate (↑) Gamma-glutamyl Amino Acid: gamma-glutamylglutamine (↑), gamma-glutamylthreonine (↑), gamma-glutamylvaline (↑) Glycolysis, Gluconeogenesis, and Pyruvate Metabolism: glucose (↑) Fructose, Mannose and Galactose Metabolism: mannose (↑) Aminosugar Metabolism: N-acetyl-glucosamine 1-phosphate (↑), N-acetylneuraminate (↑), erythronate (↑) TCA Cycle: alpha-ketoglutarate (↑) Polyunsaturated Fatty Acid (n3 and n6): eicosapentaenoate (EPA; 20:5 n3) (↑), docosahexaenoate (DHA; 22:6 n3) (↑) Fatty Acid, Dicarboxylate: 2-hydroxyglutarate (↑), 3-carboxy-4-methyl-5-propyl-2-furanpropanoate (CMPF) (↑) Fatty Acid Metabolism(Acyl Carnitine): acetylcarnitine (C2) (↑), hexanoylcarnitine (C6) (↑), palmitoylcarnitine (C16) (↑) Phospholipid Metabolism: glycerophosphorylcholine (GPC) (↑), glycerophosphoethanolamine (↑), 1, 2-dipalmitoyl-GPC (16:0/16:0) (↑), 1-stearoyl-2-arachidonoyl-GPC (18:0/20:4) (↑), 1-palmitoyl-2-arachidonoyl-GPC (16:0/20:4n6) (↑), 1-stearoyl-2-arachidonoyl-GPI (18:0/20:4) (↑), 1-stearoyl-2-arachidonoyl-GPE (18:0/20:4) (↑), 1-palmitoyl-2-stearoyl-GPC (16:0/18:0) (↑), 1-stearoyl-2-oleoyl-GPG (18:0/18:1) (↑), 1-stearoyl-2-linoleoyl-GPS (18:0/18:2) (↑)Phosphatidylserine (PS): 1-stearoyl-2-arachidonoyl-GPS (18:0/20:4) (↑), 1-stearoyl-2-oleoyl-GPS (18:0/18:1) (↑) Lysolipid: 1-palmitoyl-GPC (16:0) (↑), 1-stearoyl-GPC (18:0) (↑), 1-palmitoyl-GPE (16:0) (↑), 1-stearoyl-GPE (18:0) (↑), 1-linoleoyl-GPE (18:2) (↓), 1-stearoyl-GPI (18:0) (↑), 1-stearoyl-GPS (18:0) (↑) Plasmalogen: 1-(1-enyl-palmitoyl)-2-palmitoyl-GPC (P-16:0/16:0) (↑), 1-(1-enyl-palmitoyl)-2-arachidonoyl-GPE (P-16:0/20:4) (↑), 1-(1-enyl-palmitoyl)-2-arachidonoyl-GPC (P-16:0/20:4) (↑), 1-(1-enyl-stearoyl)-2-arachidonoyl-GPE (P-18:0/20:4) (↑) Lysoplasmalogen: 1-(1-enyl-palmitoyl)-GPE (P-16:0) (↑), 1-(1-enyl-oleoyl)-GPE (P-18:1) (↑), 1-(1-enyl-stearoyl)-GPE (P-18:0) (↑) Glycerolipid Metabolism: glycerophosphoglycerol (↑) Diacylglycerol: oleoyl-arachidonoyl-glycerol (18:1/20:4) (↑), stearoyl-arachidonoyl-glycerol (18:0/20:4) (↑) Sphingolipid Metabolism: N-palmitoyl-sphingadienine (d18:2/16:0) (↑), N-behenoyl-sphingadienine (d18:2/22:0) (↑), behenoyl sphingomyelin (d18:1/22:0) (↑), tricosanoyl sphingomyelin (d18:1/23:0) (↑), lignoceroyl sphingomyelin (d18:1/24:0) (↑), sphingomyelin (d18:2/16:0, d18:1/16:1) (↑), sphingomyelin (d18:1/20:0, d16:1/22:0) (↑), sphingomyelin (d18:1/22:1, d18:2/22:0, d16:1/24:1) (↑), sphingosine (↑), glycosyl-N-palmitoyl-sphingosine (d18:1/16:0) (↑), hexadecasphingosine (d16:1) (↑), sphingadienine (↑) Ceramides: ceramide (d14:1/22:0, d16:1/20:0) (↑), ceramide (d18:1/14:0, d16:1/16:0) (↑), ceramide (d18:1/17:0, d17:1/18:0) (↑), ceramide (d18:1/20:0, d16:1/22:0, d20:1/18:0) (↑) Purine Metabolism, (Hypo)Xanthine/Inosine containing: xanthosine (↑) Pyrimidine Metabolism, Uracil containing: uridine (↑), uracil (↑), pseudouridine (↑) Nicotinate and Nicotinamide Metabolism: N1-Methyl-2-pyridone-5-carboxamide (↑), N1-Methyl-4-pyridone-3-carboxamide (↑) Drug: oxypurinol (↑) Chemical: N-methylpipecolate (↑)
8. Bervoets et.al (2018)^Citation25	L-Histidine (↓), L-Isoleucine (↓), L-Histidine + -N^+(CH3)3 of choline head group in SM/PC (↓), Lipids: -CH2-C=O and -CH2-CH=CH- in fatty acid chain (↑), L-Glutamine (↓), L-Lysine + L-Leucine (↓), L-Lactate (↑), L-Valine + L-Isoleucine (↓)
9. Bagheri et.al (2018)^Citation26	comparing MUO to MHO, MUO phenotype was not associated with any of the assessed metabolites.
10. Zhong et.al (2017)^Citation27	(↑) Alanine, Trans-4-hydroxyproline, N-alpha-acetyl-L-lysine, Leucine/isoleucine, Glutamic acid, Creatine, Cysteine, Kynurenine, Inosine-5ʹ-diphosphate, Urate, Inosine, Tryptophan, Methionine, D-glucosamine-6-sulfate, (2R,3R)-(-)-2,3-butanediol
11. Allam-Ndoul et.al (2016)^Citation29	Acylcarnitines: C0 (↑), C3 (↑) C14:1-OH (↓) Phosphatidylcholines diacyl: C32:1 (↑), C34:1 (↑), C34:2 (↑), C34:3 (↑), C36:0 (↓), C36:4 (↑), C38:0 (↓), C38:3 (↑), C40:1 (↓), C40:3 (↓), C40:4 (↑), C40:5 (↑), C42:0 (↓), C42:1 (↓), C42:6 (↓) Phosphatidylcholines acyl-alkyl: C34:2 (↓), C34:3 (↓), C36:2 (↓), C36:3 (↓), C40:1 (↓), C40:2 (↓), C40:3 (↓), C40:4 (↓), C40:5 (↓), C40:6 (↓), C40:2 (↓), C42:3 (↓), C42:4 (↓), C42:5 (↓), C44:5 (↓), C44:6 (↓) SM(OH): C16:1 (↓), C22:1 (↓), C22:2 (↓), C24:1 (↓) Sphingomyelins: C16:0 (↓), C24:0 (↓), C24:1 (↓) Amino acids: Leucine (↑), Isoleucine (↑), Valine (↑)
12. Gao et.al (2016)^Citation28	Leucine (↑), Isoleucine (↑), Valine (↑), Alpha-aminoadipic acid (↑), Propionylcarnitine (↑)
13. Ni et.al (2015)^Citation30	FFAs: TFA (↑), SFA (↑), C8:0 (↑), C10:0 (↑), C12:0 (↑), C14:0 (↑), C15:0 (↑), C16:0 (↑), C17:0 (↑), C18:0 (↑), C19:0 (↑), C20:0 (↑), C22:0 (↑), C24:0 (↑), C14:0 iso (↑), C15:0 iso (↑), C16:0 iso (↑), C17:0 iso (↑), C18:0 iso (↑), MUFA (↑), C14:1 n5 (↑), C14:1 t9 (↑), C16:1 n9 (↑), C16:1 n7 (↑), C16:1 t9 (↑), C17:1 n7 (↑), C18:1 n9 (↑), C18:1 t9 (↑), C19:1 n9 (↑), C20:1 n9 (↑), C24:1 n9 (↑), n3PUFA (↑), C18:3 n3 (↑), C20:5 n3 (↑), C22:3 n3 (↑), C22:5 n3 (↑), C22:6 n3 (↑), n6PUFA (↑), C18:2 n6 (↑), C18:3 n6 (↑), C20:2 n6 (↑), C20:3 n6 (↑), C20:4 n6 (↑), C22:2 n6 (↑), C22:4 n6 (↑), C22:5 n6 (↑)
14. Chen et.al (2015)^Citation31	L-Kynurenine (↑), Glycerophosphocholine (↓), N-Acetylserine (↑), Decanoylcarnitine (↑), L-Alloisoleucine/L-Norleucine/L-Isoleucine (↑), Hexanoylcarnitine (↑), 5, 6-Dihydrothymine (↑), Glycerol 1-phosphate (↓), Glycolic acid (↓), Tagatose (↓), Methyl palmitate (↑), Uric acid (↑), Dioctyl phthalate (↑), Phosphoglycolic acid (↑), L-Threonine (↓), Palmitic acid (↑), Stearic acid (↓), L-Valine (↑), Benzoic acid (↓), N-Methyl-DL-glutamic acid (↑), L-(+) Lactic acid (↑), L-Tyrosine (↑), Isopropyl beta-D-1-thiogalactopyranoside (↑)
15. Böhm et.al (2014)^Citation34	Intracellular differences: Aspartate (↓), Hexose (↑), Glutamine (↑), Histidine (↑), Spermidine (↑), lysophosphatidylcholine C18:0 (↑), Phosphatidylcholine acyl: C32:3 (↑), C34:4 (↑), C36:4 (↑), C36:5 (↑) Sphingolipid C16:1 (↑) Extracellular milieu: Stearic acid (↓), Linoleic acid (↑), Arachidonic acid (↑), 15-hydroxy-eicosatetraenoic acid (↑), Docosahexaenoic acid (↑), Serotonin(↑), Phosphatidylcholine acyl: C32:0 (↑), C32:3 (↓), C36:6 (↓) Phosphatidylcholine ether side chain: C34:3 (↓), C42:2 (↑) Sphingolipids: C20:2 (↓), C22:3 (↑) Plasma: Acylcarnitine: C16 (↓), C18:1 (↓) Adrenic acid (↓), Cervonic acid [=DHA] (↓), Lysophosphatidylcholine: C16:0 (↓), C16:1 (↓), C18:1 (↓), C20:3 (↓), C20:4 (↓) Phosphatidylcholine ether side chain: 36:4 (↓), 36:5 (↓), 38:5 (↓),38:6 (↓) Sphingolipids: C26:0 (↓), Glutamic acid (↑), Hexosephosphate (↓)
16. Badoud et.al (2014)^Citation35	Lysine (↓), Hydroxyproline (↓) metabolites and/or metabolite ratios: glutamic acid-to-lysine ratio, glutamic acid-to-ornithine, the glutamic acid-to-carnitine ratio, the glutamic acid-to-hydroxyproline ratio, the tyrosine-to-hydroxyproline ratio, the glutamic acid-to-cystine ratio, and the glutamic acid-to-serine ratio, hydroxyproline
17. Perreault et.al (2014)^Citation32	Fatty acid: Saturated: TG-Myristic Acid (↑), TG-Stearic Acid (↓) Polyunsaturated: PL-Arachidonic Acid (↓)
18. Wiklund et.al (2014)^Citation33	Factor (↑) (leucine, Isoleucine, Valine, Tyrosine, Phenylalanine, Orosomucoid); Factor (↑) (Total fatty acids, Omega-6 fatty acids, Omega7 and 9 fatty acids, Linoleic acid, Mono-Unsaturated fatty acids, Total Phosphoglycerides, Total Phosphocholines)
19. Batch et.al (2013)^Citation36	BCAA related (↑) (Phenylalanine, Leucine/Isoleucine, Valine, Tyrosine, Methionine, Alanine, Histidine) Various metabolites (↑) (C5:1, Non Esterified Fatty Acids, Glutamate/glutamine, Ornithine, Arginine (-), Histidine (-)) Short chain acylcarnitines (↑) (C4/Ci4, C3, C5S) Various metabolites (↑) (Proline, Citruline, C22 Acylcarnitine)
20. Ni et.al (2015)^Citation30	FFA: SFA: C24:0 (↑) MUFA: C16:1 n7 (↑), C18:1 n9 (↑) PUFA, n3:C22:5 n3 (↑) PUFA, n6:C20:2 n6 (↑), C20:3 n6 (↑)

Abbreviations: ApoA-I, apolipoprotein A-I; ApoB, apolipoprotein B; HDL-C, total cholesterol in HDL; HDL2-C, total cholesterol in HDL2; LDL-TG, triglycerides in LDL; LDL, low-density lipoprotein; Remnant-C, remnant cholesterol (non-HDL, non-LDL-cholesterol); TG-PG ratio, ratio of triglycerides to phosphoglycerides; TG, total triglycerides; VLDL-C, total cholesterol in VLDL; VLDL-TG, triglycerides in VLDL; HDL-TG, triglycerides in HDL; lysoPEs, lysophosphatidylethanolamines; lysoPCs, lysophosphatidylcholines; FA, fatty acids; TFA, total fatty acids; SFA, saturated FAs; PUFA, polyunsaturated fatty acids; MUFA, monounsaturated fatty acids; PC, phosphatidylcholine; SM, sphingomyelin; BCAA, branched-chain amino acids; PL, phospholipid; FFAs, free fatty acids.

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