Insulin resistance and inflammation predict kinetic body weight changes in response to dietary weight loss and maintenance in overweight and obese subjects by using a Bayesian network approach.

BACKGROUND: The ability to identify obese subjects who will lose weight in response to energy restriction is an important strategy in obesity treatment. OBJECTIVE: We aimed to identify obese subjects who would lose weight and maintain weight loss through 6 wk of energy restriction and 6 wk of weight maintenance. DESIGN: Fifty obese or overweight subjects underwent a 6-wk energy-restricted, high-protein diet followed by another 6 wk of weight maintenance. Network modeling by using combined biological, gut microbiota, and environmental factors was performed to identify predictors of weight trajectories. RESULTS: On the basis of body weight trajectories, 3 subject clusters were identified. Clusters A and B lost more weight during energy restriction. During the stabilization phase, cluster A continued to lose weight, whereas cluster B remained stable. Cluster C lost less and rapidly regained weight during the stabilization period. At baseline, cluster C had the highest plasma insulin, interleukin (IL)-6, adipose tissue inflammation (HAM56+ cells), and Lactobacillus/Leuconostoc/Pediococcus numbers in fecal samples. Weight regain after energy restriction correlated positively with insulin resistance (homeostasis model assessment of insulin resistance: r = 0.5, P = 0.0002) and inflammatory markers (IL-6; r = 0.43, P = 0.002) at baseline. The Bayesian network identified plasma insulin, IL-6, leukocyte number, and adipose tissue (HAM56) at baseline as predictors that were sufficient to characterize the 3 clusters. The prediction accuracy reached 75.5%. CONCLUSION: The resistance to weight loss and proneness to weight regain could be predicted by the combination of high plasma insulin and inflammatory markers before dietary intervention.

Differential effects of macronutrient content in 2 energy-restricted diets on cardiovascular risk factors and adipose tissue cell size in moderately obese individuals: a randomized controlled trial.

BACKGROUND: The most effective and safe dietary approach for weight loss and its impact on the metabolic functions and morphology of adipose tissue remain unclear. OBJECTIVES: We evaluated whether an energy-restricted high-protein diet with a low glycemic index and soluble fiber (LC-P-LGI) would be more effective than a low-calorie conventional diet (LC-CONV) on weight loss and related metabolic risk factors. We further determined factors that may influence adipocyte size during energy restriction. DESIGN: Thirteen obese participants were randomly assigned in a crossover design to 2 periods of a 4-wk hypocaloric diet as either LC-P-LGI or LC-CONV, separated by 8-wk washout intervals. RESULTS: In comparison with the LC-CONV diet, the main effect of the LC-P-LGI diet was a greater decrease in adipocyte diameter (P = 0.048), plasma plasminogen activator inhibitor protein-1 (P = 0.019), vascular endothelial growth factor (P = 0.032), and interferon-γ inducible protein 10 (P = 0.010). Whereas fasting plasma glucose and high-sensitivity C-reactive protein decreased only after the LC-P-LGI diet, with no differences between diets, fasting plasma insulin and insulin resistance were lower after the LC-CONV diet. The diet results did not differ for body composition and lipid variables. Kinetic modifications in adipocyte diameter were associated with metabolic variables and genes implicated in adipocyte proliferation, apoptosis, and angiogenesis. CONCLUSIONS: In comparison with the LC-CONV diet, the LC-P-LGI diet was associated with improvement in some cardiometabolic risk factors and greater reduction in adipocyte size. Profiles of genes involved in inhibiting adipogenesis and angiogenesis, but increasing apoptosis, were correlated with decreased adipocyte size. This study provides insight into the adipose tissue-remodeling changes that induce regulation of adipocyte size during dietary weight loss. This trial was registered at clinicaltrials.gov as NCT01312740.

Human adipose tissue macrophages: m1 and m2 cell surface markers in subcutaneous and omental depots and after weight loss.

CONTEXT: Macrophages accumulate in adipose tissue and possibly participate in metabolic complications in obesity. Macrophage number varies with adipose tissue site and weight loss, but whether this is accompanied by phenotypic changes is unknown. OBJECTIVE: The objective of the study was to characterize the activation state of adipose tissue macrophages in human obesity. DESIGN/SETTING: We performed a single-center prospective study. PARTICIPANTS/INTERVENTIONS: Paired biopsies of sc and omental adipose tissue were obtained during gastric surgery in 16 premenopausal obese women (aged 41.1 +/- 8.6 yr; body mass index 43.8 +/- 3.4 kg/m(2)). Subcutaneous adipose tissue biopsies were obtained 3 months later in obese subjects and in 10 nonobese women (aged 43.3 +/- 3.5 yr; body mass index 22.5 +/- 0.75 kg/m(2)). The number of macrophages stained with CD40, CD206, and CD163 surface markers was determined by immunochemistry. MAIN OUTCOMES: The number of CD40(+) macrophages significantly increased with obesity and in omental vs. sc adipose tissue in obese women. No significant changes in CD163(+) and CD206(+) macrophage counts was found with obesity and fat pad anatomical location. Three months after gastric surgery, the ratio of CD40(+) to CD206(+) macrophages was 2-fold lower than before surgery in the sc adipose tissue of obese subjects (P < 0.001) due to a concomitant decrease of CD40(+) and increase of CD206(+) macrophages counts. CONCLUSION: We suggest that the activation state of adipose tissue macrophages is weighted toward M1 over M2 status in obese subjects and switch to a less proinflammatory profile 3 months after gastric bypass.

Deficiency and inhibition of cathepsin K reduce body weight gain and increase glucose metabolism in mice.

OBJECTIVE: Previous studies demonstrated increased levels of cysteine proteases cathepsins in serum and adipose tissues from obese patients. We now provide evidence from a mouse model of obesity to suggest a direct participation of cathepsin K (CatK) in mouse body weight gain and glucose metabolism. METHODS AND RESULTS: Using real-time polymerase chain reaction, we detected 12-fold increase in CatK transcripts after adipogenesis of human preadipocytes. Using an immunohistology analysis, we consistently observed high levels of CatK expression in adipose tissues from obese humans and mice. Selective inhibition of CatK activity blocked the lipid accumulation in human and mouse preadipocytes. In mice, CatK deficiency reduced significantly diet-induced body weight gain and serum glucose and insulin levels. Similar results were obtained in diet-induced and genetically created (ob/ob) obese mice after animals were treated with a CatK-selective inhibitor. Mechanistic study demonstrated a role for CatK in degrading fibronectin, a matrix protein that controls adipogenesis. Deficiency or inhibition of CatK leads to fibronectin accumulation in muscle and adipose tissues. CONCLUSIONS: This study demonstrates an essential role of CatK in adipogenesis and mouse body weight gain, possibly via degradation of fibronectin, thus suggesting a novel therapeutic strategy for the control of obesity by regulating CatK activity.

IL-1 receptor antagonist in metabolic diseases: Dr Jekyll or Mr Hyde?

Interleukin-1 receptor antagonist (IL-1ra) has been shown to play a crucial role in the prevention of various inflammatory diseases. There is also convincing evidence that IL-1ra is able to counteract inflammatory effects of IL-1 members implicated in insulin resistance and diabetes. However, the use of knock-out animal models provides evidence to the contrary and the role of IL-1ra in obesity-linked anomalies remains controversial. This minireview gets an insight into recent findings on the implication of IL-1ra and its gene polymorphism in diabetes and obesity, discusses the potential dual effects of IL-1ra observed in different models, and comments on future directions.

Thymulin evokes IL-6-C/EBPbeta regenerative repair and TNF-alpha silencing during endotoxin exposure in fetal lung explants.

Chorioamnionitis is associated with increased risks of perinatal respiratory failure; however, components of the inflammatory acute-phase response are known to actively promote lung maturation. To manipulate this relationship, we examined the effect of the thymic immunomodulator thymulin on fetal lung mesenchyme-epithelial differentiation during exposure to Escherichia coli lipopolysaccharide (LPS). Gestation day 14 fetal rat lung explants were cultured for 96 h at fetal (23 mmHg) or ambient (142 mmHg) Po(2). Airway surface complexity (ASC, perimeter/ radical area(2)) was greater at fetal vs. ambient Po(2); however, exposure to 0.1-50 microg/ml LPS significantly raised ASC at 2 microg/ml in ambient Po(2) explants. LPS (50 microg/ml) depressed ASC in both conditions to untreated ambient Po(2) control values without changes in necrosis or apoptosis. To manipulate LPS-evoked TNF-alpha and IL-6 release, we exposed explants and A549 cells to combinations of 50 microg/ml LPS, 10 microM ZnCl(2), and 0.1-1,000 ng/ml thymulin at either Po(2). Thymulin+Zn(2+) suppressed and potentiated LPS-evoked TNF-alpha and IL-6 release, yielding an IC(50(TNF-alpha)) of 0.5 +/- 0.01 ng/ml and EC(50(IL-6)) of 1.4 +/- 0.3 ng/ml in A549 cells. This was accompanied by activation of the p38 MAPKMAPKAP-K2 pathway with sustained expression of TNF-alpha and IL-6 transcripts at ambient Po(2). LPS+thymulin+Zn(2+)-treated explants showed proliferation of CCAAT-enhancer binding protein-beta (C/EBPbeta) and fibroblast growth factor-9 immunoreactive mesenchyme, which was abolished by IL-6 antisense oligonucleotides. The posttranscriptional suppression of immunogenic TNF-alpha synthesis coupled with raised IL-6 and C/EBPbeta-dependent mesenchyme proliferation suggests a role for bioactive thymulin in regulating regenerative repair in the fetal lung.