Table 5.
Effects of weight loss or gain on AT inflammation and insulin sensitivity in humans: evidence from surgical and dietary intervention studies.
| Baseline characteristics | Intervention | Assessment of AT inflammation | Assessment of insulin sensitivity | Measures of ectopic fat deposition | Outcome | Reference |
|---|---|---|---|---|---|---|
| n=17F 29–59 years 33–57 kg/m2 |
RYGB | SAT sample obtained at surgery and 3-months
post surgery. Gene expression: MCP1, CSF3, HIF1A, PLAUR IHC: HAM56, CD68 |
QUICKI | None | Three months following surgery subjects exhibited mean weight loss of 22.1 kg (17%), significant improvements in insulin sensitivity, and reductions in CD68+HAM56+ ATM in SAT. Expression of MCP1, CSF3, HIF1A, and PLAUR mRNA in SAT post-surgery was significantly lower compared to pre-surgery values. No correlation was observed between change in insulin sensitivity and change in ATM number in SAT. | (56) |
| n=50F 21–49 years 36.2±0.7 kg/m2 |
10-week energy restriction: ~70% of ETEE as HFLCD (n=25) vs. LFHCD (n=25) | SAT biopsy at baseline and 10
weeks. Gene expression: 38 genes (TNFA, ADIPOQ, IL6, PAI1) |
QUICKI | None | Subjects lost ~6.8% body weight on either diet and insulin sensitivity improved significantly. SAT expression of TNFA, ADIPOQ, IL6, and PAI1 mRNA did not change significantly with weight loss or by diet group. | (495) |
| n=22F premenopausal 35.3±1.0 kg/m2 |
Successive: 1-month VLCD (800 kcal/d), 2-month LCD (600 kcal/d deficit from ETEE), 3–4 month weight maintenance period | SAT biopsy at baseline and 1-, 2-, and 4-mths. Gene expression: 31 macrophage-specific markers | Hyperinsulinemic-euglycemic clamp | None | Insulin sensitivity increased significantly during the calorie restriction and weight maintenance phases compared to baseline concurrent with a mean weight loss of 10.2%. Expression of macrophage-specific genes was upregulated during the energy restriction phase and downregulated during weight stabilization. | (59) |
| n=16F 41.1±8.6 years 43.8±3.4 kg/m2 |
RYGB | SAT obtained at surgery and 3-mths post.
IHC: CD40, CD163, CD206, HAM56 |
QUICKI | None | At 3 months post-surgery, subjects had lost a mean 15% body weight and insulin sensitivity improved significantly. Number of HAM56+ and CD40+ cells decreased while CD206+ and CD163+ cells increased, and there was a 2-fold reduction of CD40 to CD206 ratio. | (26) |
| n=13 (6F) 35–65 years 35.1–50.8 kg/m2 |
24 week energy restriction (first 12 weeks VLCD, followed by gastric banding) | SAT sample and whole blood obtained at
baseline, 12 weeks, and 24 weeks. Flow cytometry: CD14, CD11b, CD66b, CD69, IFNγ, IL4 |
HOMA | None | At 12 weeks weight loss averaged 5%, and 13.5% by 24 weeks. HOMA showed a downward trend but changes were not significant at either time point. In SAT, macrophage number was significantly reduced after VLCD. No relationship was found between changes in immune cell activation, SAT ATM number, and improvements in HOMA. | (492) |
| n=27F 39±2 yrs 33.7±0.5 kg/m2 |
28-d VLCD (800 kcal/d), followed by 2 months of weight stabilization, then 3–4 months of weight maintenance | SAT biopsy at baseline, after calorie
restriction, and following weight stabilization. Gene expression: CD14, CD68, CD163, LYVE1 Flow cytometry: CD14, CD16, CD206 |
HOMA | None | VLCD led to significant weight loss (~10%), and significant improvements in HOMA. However, reductions in CD14+CD206+ ATM number and SAT expression of CD14, CD68, CD163 and LYVE1 mRNA were not detected until after the weight stabilization period that followed. | (250) |
| n=44M 18–55 years 18–30 kg/m2 |
56-d overfeeding (+760 kcal/d) | SAT biopsy at baseline, day 14, and day 56.
IHC (n=15): CD68 |
HOMA | None | Subjects consumed an additional 700 kcal daily and gained 3% of baseline body weight after the 56-d intervention. HOMA increased significantly. However, there was no significant change in ATM number in SAT. | (15) |
| n=34 (24F) 21–61 years 48.8±0.9 kg/m2 |
RYGB | SAT obtained at surgery, month 6, and month 12 post-surgery. Gene expression: CRP, IL6, TNFA | HOMA | None | Subjects lost 28% and 37% of body weight by months 6 and 12, respectively. HOMA decreased significantly compared to baseline by month 6 and was further reduced by month 12. No significant changes in SAT expression of IL6 or TNFA mRNA were detected at either 6 or 12 months post-surgery. In contrast, SAT expression of CRP mRNA decreased significantly 6 months after surgery and declined further at 12 months post-surgery. | (368) |
| n=23 (12F) 25–50 years 27.7±1.7 kg/m2 |
6-mo energy restriction (75% of ETEE) (n=12) vs. control (weight maintenance) (n=11) | SAT biopsy at baseline and 24 wks. Gene expression: TNFA, IL6, CD68, MIF, MCP1, PAI1, ADIPOQ |
FS-IVGTT | None | Subjects in CR group lost ~10% body weight and insulin sensitivity tended to improve. SAT expression of IL6, TNFA, CD68, MIF, MCP1, PAI1, and ADIPOQ mRNA did not change significantly with weight loss and did not differ by diet group. | (456) |
| n=13F 40.8±8.4 years 42.3±4.1 kg/m2 |
VSG | SAT biopsy at baseline (pre-surgery), month 6 (n=11), month 12 (n=11), and month 24 (n=8) post-surgery. Gene expression: 45 inflammation-related genes | HOMA | None | Subjects’ mean BMI decreased by 21% and 26% at months 6 and 12 post-surgery, respectively and tended to increase again by month 24. HOMA did not change to a significant degree at any time point compared to pre-surgery values. At 6 months post-surgery, SAT expression of inflammatory gene mRNAs were largely unchanged compared to baseline. By 12 and 24 months, the downregulation of some inflammation-related genes was more pronounced suggesting that VSG reduced the expression profile of inflammatory cytokines and chemokines in SAT. | (468) |
| n=16 (11F) 46±5.8 years 58.9±9.6 kg/m2 |
Two-step bariatric surgery: baseline VSG, RYGB at 12 months | SAT and VAT samples obtained at both
surgeries. Gene expression: FAS, FASL |
HOMA | None | Following VSG, BMI decreased by 25% and insulin sensitivity improved significantly. VAT and SAT expression of FAS mRNA decreased significantly by 40% and 33%, respectively. | (46) |
| n=29M 26.8±5.4 years 25.5±2.3 kg/m2 |
8-week overfeeding: 140% ETEE | SAT biopsy at baseline and 8
weeks. Gene expression: CD68, IL6, CCL2, ADIPOQ, NFKB, VCAM1 IHC: CD68 |
Hyperinsulinemic-euglycemic clamp | Intrahepatic and intramyocellular lipid: MRS | Subjects gained 10% body weight, and intrahepatic lipid content increased significantly while intramyocellular lipid content did not change. Insulin sensitivity decreased significantly. However, there was no change in SAT expression of CD68, IL6, CCL2, ADIPOQ, NFKB, or VCAM1 mRNA with overfeeding, nor was there a change in the numbers of ATM or CLS observed in SAT. | (212, 455) |
| n=7 (5F) 52.6±6.2 years 38.9±4.9 kg/m2 |
RYGB | SAT biopsy at baseline and at 7% weight loss
(13±2 days post-surgery). Gene expression: TNFA, IL1B, IL6, MCP1, ICAM1, ADIPOQ Flow Cytometry: ATM (CD14+CD206+CD11c+), neutrophils (CD15+CD16+), DC (CD1c+CD11c+), and T cells (CD3+CD4+CD8+) |
HOMA | None | Subjects lost 7% of initial body weight within the first 2 weeks following surgery and exhibited significant improvement in insulin sensitivity. SAT expression of TNFA, IL6, MCP1, and ICAM1 mRNA did not differ from baseline. In contrast, expression of IL1B was elevated, and ADIPOQ reduced, both significantly. Numbers of neutrophils in SAT exhibited significant increases over baseline, while ATM, DC, and T cell-numbers trended upward. | (254) |
| n=40 44±12 years 37.9±4.4 kg/m2 |
Energy restriction to achieve 5% weight loss (n=10) vs. 10% and 15% progressive weight loss (n=10) vs. weight maintenance (n=20) | SAT biopsy at baseline and 6-months (for
weight maintenance) or 3-weeks post weight stabilization. Gene expression: TNFA, IL6, CCL3, RANTES, CD68, EMR1, microarray |
Hyperinsulinemic-euglycemic clamp with stable isotope-labeled tracer infusion | Intrahepatic TG content: MRS | 5% weight loss decreased intrahepatic TG content, improved beta-cell function and insulin sensitivity in liver, SAT, and muscle while SAT inflammation remained unchanged. 11–16% weight loss was associated with a reduction in SAT inflammation while intrahepatic TG content decreased in a significant and linear manner with progressive weight loss along with further improvements in beta-cell function and insulin sensitivity in muscle. | (286) |
| n=17F 35±7 years 32.6±3.6 kg/m2 |
28-d energy restriction (800 kcal/d) | SAT biopsy at baseline, day 2, and day 28.
Gene expression: 14 macrophage and cytokine genes |
HOMA, QUICKI | None | Subjects lost ~9% body weight after 28-d intervention, and insulin sensitivity improved significantly. SAT expression of macrophage markers CD163, MSR1, IRF5, and CCR2 mRNA was significantly increased by day 28 and expression of IL8, MCP1, TNFA, IL6, and IL10 mRNA tended to increase but changes were not significant. | (436) |
| N=55 (38F) 44.5±11.0 years 53.6±7.3 kg/m2 |
VSG | SAT, VAT, and liver biopsy at baseline and after 1 year | HOMA (n=55) Hypersinsulinemic euglycemic clamp (n=11) |
None (But reduction in inflammation markers in liver) |
VSG similarly reduced body weight, body fat mass, and HOMA significantly after 1 year, independent of whether the weight loss was associated with a reduction in inflammation markers or ATM in VAT. | (417) |
| n=17 46.2±7.5 kg/m2 |
RYGB (n=7) VSG (n=10) |
SAT biopsy at baseline, 1 month, and
6–12 months after surgery. Gene expression: TNFA, IL1B, IL6, ADIPOQ Flow Cytometry: ATM (CD14+CD206+CD11c+), neutrophils (CD15+CD16+), DC (CD1c+CD11c+), and T cells (CD3+CD4+CD8+) |
HOMA Matsuda-ISI based on FS-OGTT |
None | In the first month, subjects lost ~10% of initial body weight, and HOMA was significantly reduced, with no change in the Matsuda-ISI. SAT expression of TNFA, IL1B, IL6, and ADIPOQ mRNA did not change from baseline, nor were there changes in the numbers of ATM, DC, or CD4+ T cells. The number of neutrophils and CD8+ T cells were elevated at 1-month post-surgery. By 12 months, subjects lost 26% of initial body weight, with an increase in Matsuda-ISI. SAT expression of TNFA, IL1B, and IL6 mRNA did not differ from baseline, while ADIPOQ declined. Neutrophils, DC, and CD8+ T cells all consistently exhibited increased numbers in AT relative to baseline, while ATM and CD4+ T cells also increased. | (162) |
Abbreviations: ADIPOQ, adiponectin; ATM, adipose tissue macrophage; BMI, body mass index; CCL2, C-C motif chemokine ligand 2 (MCP1); CCL3, C-C motif chemokine ligand 3; CCR2, C-C motif chemokine receptor type 2; CD, cluster of differentiation; CRP, C-reactive protein; CSF3, colony-stimulating factor-3; DC, dendritic cells; EMR1, EGF-like module-containing mucin-like hormone receptor-like 1; ETEE, estimated total energy expenditure; FAS, death receptor CD95; FASL, Fas-ligand; FS-OGTT: frequently sampled oral glucose tolerance test; FS-IVGT, frequently sampled-intravenous glucose tolerance test; T HFLCD, high-fat low-carbohydrate diet; HAM56, human alveolar macrophage 56; HIF1A, hypoxia-inducible factor-1α; HOMA, homeostasis model assessment; ICAM1, intracellular adhesion molecule 1; IHC, immunohistochemistry; IFNγ, interferon-γ; IL, interleukin; IRF5, interferon regulatory factor 5; ISI: Insulin sensitivity index; LCD, low-calorie diet; LFHCD, low-fat high-carbohydrate diet; LYVE1, lymphatic vessel endothelial hyaluronan receptor-1; MCP1, monocyte chemotactic protein-1; MIF, macrophage migration inhibitory factor; MRS, magnetic resonance spectroscopy; MSR1, macrophage scavenger receptor 1; NFKB, nuclear factor-κB; PAI1, plasminogen activator inhibitor 1; PLAUR, plasminogen activator urokinase receptor; QUICKI, quantitative insulin sensitivity check index; RANTES, regulated on activation normal T cell expressed and secreted; RYGB, Roux-en-Y gastric bypass; SAT, subcutaneous adipose tissue; TG, triglyceride; TNFα, tumor necrosis factor-α; VCAM1, vascular cell adhesion molecule-1; VLCD, very-low-calorie diet; VSG, vertical sleeve gastrectomy; VAT, visceral adipose tissue