Diurnal fluctuation of leukocyte G6PD activity. A possible explanation for the normal neutrophil bactericidal activity and the low incidence of pyogenic infections in patients with severe G6PD deficiency in Israel

Acute hemolytic anemia associated with red blood cell (RBC) glucose-6-phosphate dehydrogenase (G6PD) deficiency is commonly encountered in the Mediterranean basin. Nevertheless, concomitant clinical evidence of white blood cell G6PD deficiency is extremely rare in Israel. This study sought to assess simultaneously levels of G6PD activity in polymorphonuclear leukocytes (PMN) and in red blood cells (RBC) of patients with G6PD deficiency, including full-term newborn infants. In PMN, the correlation between G6PD activity, hexose monophosphate shunt activity, and superoxide anion release was evaluated. In G6PD-deficient patients, a parallel and significantly decreased G6PD activity was found in neutrophils (range of activity 0-4.5 IU/10(6) PMN) and erythrocytes (range of activity 0-1.8 IU/g Hb), compared with healthy controls (5-23 IU/10(6) PMN and 2.4-6.4 IU/g Hb, respectively). A positive correlation was found in PMN between the levels of G6PD activity, hexose monophosphate (HMP) shunt activity, and superoxide anion release (p <0.01). Nevertheless, all patients' bactericidal activity of neutrophils remained in the range of healthy controls. Although many episodes of acute hemolytic anemia were recorded, no increased incidence of pyogenic infections was observed in any group of patients investigated. Neutrophil and erythrocyte G6PD levels were re-assessed in some of these patients several times a day. A significant diurnal fluctuation of the enzyme activity was found. It is speculated that the patients produce fluctuating daily quantities of NADPH, sufficient to initiate the neutrophil respiratory burst and to achieve normal bactericidal activity, necessary to prevent the development of microbial infection

Interleukin-1β regulates fat-liver crosstalk in obesity by auto-paracrine modulation of adipose tissue inflammation and expandability

The inflammasome has been recently implicated in obesity-associated dys-metabolism. However, of its products, the specific role of IL-1β was clinically demonstrated to mediate only the pancreatic beta-cell demise, and in mice mainly the intra-hepatic manifestations of obesity. Yet, it remains largely unknown if IL-1β, a cytokine believed to mainly function locally, could regulate dysfunctional inter-organ crosstalk in obesity. Here we show that High-fat-fed (HFF) mice exhibited a preferential increase of IL-1β in portal compared to systemic blood. Moreover, portally-drained mesenteric fat transplantation from IL-1βKO donors resulted in lower pyruvate-glucose flux compared to mice receiving wild-type (WT) transplant. These results raised a putative endocrine function for visceral fat-derived IL-1β in regulating hepatic gluconeogenic flux. IL-1βKO mice on HFF exhibited only a minor or no increase in adipose expression of pro-inflammatory genes (including macrophage M1 markers), Mac2-positive crown-like structures and CD11b-F4/80-double-positive macrophages, all of which were markedly increased in WT-HFF mice. Further consistent with autocrine/paracrine functions of IL-1β within adipose tissue, adipose tissue macrophage lipid content was increased in WT-HFF mice, but significantly less in IL-1βKO mice. Ex-vivo, adipose explants co-cultured with primary hepatocytes from WT or IL-1-receptor (IL-1RI)-KO mice suggested only a minor direct effect of adipose-derived IL-1β on hepatocyte insulin resistance. Importantly, although IL-1βKOs gained weight similarly to WT-HFF, they had larger fat depots with similar degree of adipocyte hypertrophy. Furthermore, adipogenesis genes and markers (pparg, cepba, fabp4, glut4) that were decreased by HFF in WT, were paradoxically elevated in IL-1βKO-HFF mice. These local alterations in adipose tissue inflammation and expansion correlated with a lower liver size, less hepatic steatosis, and preserved insulin sensitivity. Collectively, we demonstrate that by promoting adipose inflammation and limiting fat tissue expandability, IL-1β supports ectopic fat accumulation in hepatocytes and adipose-tissue macrophages, contributing to impaired fat-liver crosstalk in nutritional obesity

Circulating Blood Monocyte Subclasses and Lipid-Laden Adipose Tissue Macrophages in Human Obesity

<div><p>Background</p><p>Visceral adipose tissue foam cells are increased in human obesity, and were implicated in adipose dysfunction and increased cardio-metabolic risk. In the circulation, non-classical monocytes (NCM) are elevated in obesity and associate with atherosclerosis and type 2 diabetes. We hypothesized that circulating NCM correlate and/or are functionally linked to visceral adipose tissue foam cells in obesity, potentially providing an approach to estimate visceral adipose tissue status in the non-surgical obese patient.</p><p>Methods</p><p>We preformed <i>ex-vivo</i> functional studies utilizing sorted monocyte subclasses from healthy donors. Moreover, we assessed circulating blood monocyte subclasses and visceral fat adipose tissue macrophage (ATM) lipid content by flow-cytometry in paired blood and omental-fat samples collected from patients (n = 65) undergoing elective abdominal surgery.</p><p>Results</p><p><i>Ex-vivo</i>, NCM and NCM-derived macrophages exhibited lower lipid accumulation capacity compared to classical or intermediate monocytes/-derived macrophages. Moreover, of the three subclasses, NCM exhibited the lowest migration towards adipose tissue conditioned-media. In a cohort of n = 65, increased %NCM associated with higher BMI (r = 0.250,p<0.05) and ATM lipid content (r = 0.303,p<0.05). Among patients with BMI≥25Kg/m², linear regression models adjusted for age, sex or BMI revealed that NCM independently associate with ATM lipid content, particularly in men.</p><p>Conclusions</p><p>Collectively, although circulating blood NCM are unlikely direct functional precursor cells for adipose tissue foam cells, their increased percentage in the circulation may clinically reflect higher lipid content in visceral ATMs.</p></div