Kurt Hong

Circulating fibrocytes traffic to the lungs in response to CXCL12 and mediate fibrosis

Previous reports have identified a circulating pool of CD45(+) collagen I(+) CXCR4(+) (CD45(+)Col I(+)CXCR4(+)) cells, termed fibrocytes, that traffic to areas of fibrosis. No studies have demonstrated that these cells actually contribute to fibrosis, however. Pulmonary fibrosis was originally thought to be mediated solely by resident lung fibroblasts. Here we show that a population of human CD45(+)Col I(+)CXCR4(+) circulating fibrocytes migrates in response to CXCL12 and traffics to the lungs in a murine model of bleomycin-induced pulmonary fibrosis. Next, we demonstrated that murine CD45(+)Col I(+)CXCR4(+) fibrocytes also traffic to the lungs in response to a bleomycin challenge. Maximal intrapulmonary recruitment of CD45(+)Col I(+)CXCR4(+) fibrocytes directly correlated with increased collagen deposition in the lungs. Treatment of bleomycin-exposed animals with specific neutralizing anti-CXCL12 Abs inhibited intrapulmonary recruitment of CD45(+)Col I(+)CXCR4(+) circulating fibrocytes and attenuated lung fibrosis. Thus, our results demonstrate, we believe for the first time, that circulating fibrocytes contribute to the pathogenesis of pulmonary fibrosis.

Differentiation of Human Circulating Fibrocytes as Mediated by Transforming Growth Factor-β and Peroxisome Proliferator-activated Receptor γ

Fibrocytes are a distinct population of fibroblast-like progenitor cells in peripheral blood that have recently been shown to possess plasticity to differentiate along mesenchymal lineages, including commitment to myofibroblast and adipocyte cells. Here, we demonstrated that transforming growth factor (TGF) β1 drives fibrocyte-to-myofibroblast differentiation through activating Smad2/3 and SAPK/JNK MAPK pathways, which in turn stimulates α-smooth muscle actin expression. We determined that SAPK/JNK signaling acts in a positive feedback loop to modulate Smad2/3 nuclear availability and Smad2/3-dependent transcription. Conversely, fibrocyte-to-adipocyte differentiation is driven by the peroxisome proliferator-activated receptor (PPAR) γ agonist troglitazone, which is associated with cytoplasmic lipid accumulation and induction of aP2. Treatment with troglitazone also disrupted TGFβ1-activated SAPK/JNK signaling, leading to decreased Smad2/3 transactivation activity and α-smooth muscle actin expression. Interestingly, TGFβ1 was demonstrated to have reciprocal inhibition on fibrocyte differentiation to adipocytes. By activating SAPK/JNK signaling, which is normally suppressed during adipogenesis, PPARγ-dependent transactivation activity and induction of aP2 expression were disrupted. Taken together, within the context of the local microenvironmental niche, the delicate balance of PPARγ and TGFβ1 activation drives the selection of an adipocyte or myofibroblast differentiation pathway through SAPK/JNK signaling.

Characterization of human fibrocytes as circulating adipocyte progenitors and the formation of human adipose tissue in SCID mice

An increase in fat mass associated with obesity results from recruitment and differentiation of adipocyte progenitor cells. The precise origin of these cells is unknown, although accumulating evidence suggests that circulating stem cells can differentiate into cells of mesenchymal lineage. It is currently unclear whether a progenitor adipocyte population exists in circulation. One potential candidate is the fibrocyte, which may represent a common progenitor cell for several mesenchymal lineages. We demonstrate that these circulating progenitors become adipocytes when cultured under adipogenic conditions, with intracellular lipids accumulation and up‐regulation of proteins specific for adipocyte differentiation, including leptin, PPARγ, and FABP4. cDNA microarray analysis revealed gene clusters that were differentially regulated during adipogenesis of fibrocytes, which were similar to visceral and subcutaneous adipose tissue preadipocyte‐to‐adipocyte differentiation. Moreover, these progenitors engrafted and formed human adipose tissue following injection into SCID mice. Although fibrocytes express an array of chemokine receptors, we observed an up‐regulation of CCR2 expression following fibrocytes differentiation into adipocytes, which was associated with increased chemotactic response to CCL2. This paradigm supports the notion that elevated CCL2 levels in visceral adipose tissue associated with Metabolic Syndrome is a chemotactic niche, whereby fibrocytes can home to and differentiate into adipocytes to perpetuate its tissue formation.

Role of CXCR2/CXCR2 ligands in vascular remodeling during bronchiolitis obliterans syndrome

Angiogenesis and vascular remodeling support fibroproliferative processes; however, no study has addressed the importance of angiogenesis during fibro-obliteration of the allograft airway during bronchiolitis obliterans syndrome (BOS) that occurs after lung transplantation. The ELR(+) CXC chemokines both mediate neutrophil recruitment and promote angiogenesis. Their shared endothelial cell receptor is the G-coupled protein receptor CXC chemokine receptor 2 (CXCR2). We found that elevated levels of multiple ELR(+) CXC chemokines correlated with the presence of BOS. Proof-of-concept studies using a murine model of BOS not only demonstrated an early neutrophil infiltration but also marked vascular remodeling in the tracheal allografts. In addition, tracheal allograft ELR(+) CXC chemokines were persistently expressed even in the absence of significant neutrophil infiltration and were temporally associated with vascular remodeling during fibro-obliteration of the tracheal allograft. Furthermore, in neutralizing studies, treatment with anti-CXCR2 Abs inhibited early neutrophil infiltration and later vascular remodeling, which resulted in the attenuation of murine BOS. A more profound attenuation of fibro-obliteration was seen when CXCR2(-/-) mice received cyclosporin A. This supports the notion that the CXCR2/CXCR2 ligand biological axis has a bimodal function during the course of BOS: early, it is important for neutrophil recruitment and later, during fibro-obliteration, it is important for vascular remodeling independent of neutrophil recruitment.

A controlled trial of protein enrichment of meal replacements for weight reduction with retention of lean body mass

BackgroundWhile high protein diets have been shown to improve satiety and retention of lean body mass (LBM), this study was designed to determine effects of a protein-enriched meal replacement (MR) on weight loss and LBM retention by comparison to an isocaloric carbohydrate-enriched MR within customized diet plans utilizing MR to achieve high protein or standard protein intakes.MethodsSingle blind, placebo-controlled, randomized outpatient weight loss trial in 100 obese men and women comparing two isocaloric meal plans utilizing a standard MR to which was added supplementary protein or carbohydrate powder. MR was used twice daily (one meal, one snack). One additional meal was included in the meal plan designed to achieve individualized protein intakes of either 1) 2.2 g protein/kg of LBM per day [high protein diet (HP)] or 2) 1.1 g protein/kg LBM/day standard protein diet (SP). LBM was determined using bioelectrical impedance analysis (BIA). Body weight, body composition, and lipid profiles were measured at baseline and 12 weeks.ResultsEighty-five subjects completed the study. Both HP and SP MR were well tolerated, with no adverse effects. There were no differences in weight loss at 12 weeks (-4.19 ± 0.5 kg for HP group and -3.72 ± 0.7 kg for SP group, p > 0.1). Subjects in the HP group lost significantly more fat weight than the SP group (HP = -1.65 ± 0.63 kg; SP = -0.64 ± 0.79 kg, P = 0.05) as estimated by BIA. There were no significant differences in lipids nor fasting blood glucose between groups, but within the HP group a significant decrease in cholesterol and LDL cholesterol was noted at 12 weeks. This was not seen in the SP group.ConclusionHigher protein MR within a higher protein diet resulted in similar overall weight loss as the standard protein MR plan over 12 weeks. However, there was significantly more fat loss in the HP group but no significant difference in lean body mass. In this trial, subject compliance with both the standard and protein-enriched MR strategy for weight loss may have obscured any effect of increased protein on weight loss demonstrated in prior weight loss studies using whole food diets.

Fasting-mimicking diet and markers/risk factors for aging, diabetes, cancer, and cardiovascular disease

A periodic fasting diet improves markers of metabolic dysfunction, particularly in people already at risk. Fasting: More than a fad Mice that fast periodically are healthier, metabolically speaking. To explore whether fasting can help people as well, Wei et al. studied 71 people who either consumed a fasting-mimicking diet for 5 days each month for 3 months or maintained their normal diet for 3 months and then switched to the fasting schedule. The fasting-like diet reduced body weight and body fat, lowered blood pressure, and decreased the hormone IGF-1, which has been implicated in aging and disease. A post hoc analysis replicated these results and also showed that fasting decreased BMI, glucose, triglycerides, cholesterol, and C-reactive protein (a marker for inflammation). These effects were generally larger in the subjects who were at greater risk of disease at the start of the study. A larger study is needed to replicate these results, but they raise the possibility that fasting may be a practical road to a healthy metabolic system. Calorie restriction or changes in dietary composition can enhance healthy aging, but the inability of most subjects to adhere to chronic and extreme diets, as well as potentially adverse effects, limits their application. We randomized 100 generally healthy participants from the United States into two study arms and tested the effects of a fasting-mimicking diet (FMD)—low in calories, sugars, and protein but high in unsaturated fats—on markers/risk factors associated with aging and age-related diseases. We compared subjects who followed 3 months of an unrestricted diet to subjects who consumed the FMD for 5 consecutive days per month for 3 months. Three FMD cycles reduced body weight, trunk, and total body fat; lowered blood pressure; and decreased insulin-like growth factor 1 (IGF-1). No serious adverse effects were reported. After 3 months, control diet subjects were crossed over to the FMD program, resulting in a total of 71 subjects completing three FMD cycles. A post hoc analysis of subjects from both FMD arms showed that body mass index, blood pressure, fasting glucose, IGF-1, triglycerides, total and low-density lipoprotein cholesterol, and C-reactive protein were more beneficially affected in participants at risk for disease than in subjects who were not at risk. Thus, cycles of a 5-day FMD are safe, feasible, and effective in reducing markers/risk factors for aging and age-related diseases. Larger studies in patients with diagnosed diseases or selected on the basis of risk factors are warranted to confirm the effect of the FMD on disease prevention and treatment.

Insulin, hs-CRP, Leptin, and Adiponectin. An Analysis of their Relationship to the Metabolic Syndrome in an Obese Population with an Elevated Waist Circumference

BACKGROUND Various adipose tissue factors have been implicated as biomarkers of the metabolic syndrome (MS). The objective of this study was to assess which specific adipose tissue factors would discriminate the presence of MS in a strictly obese population meeting waist circumference (WC) criteria for the MS. METHODS This was a cross-sectional study of 148 subjects recruited from a university-based weight loss program prior to starting the program. Patients were eligible if they had a BMI more than 25 kg/m(2) and had WC more than 40 and 35 inches in males and females, respectively. Biomarkers measured included high sensitivity C-reactive protein (hs-CRP), leptin, adiponectin, and total insulin. RESULTS Of the total population, 33.8% satisfied criteria for the MS. Insulin was the only biomarker to consistently differentiate between presence and absence of MS in this obese population (P = 0.0001 in males, P = 0.006 in females). All biomarkers measured with the exception of leptin had a statistically significant relationship with increasing criteria for the MS. CONCLUSIONS In a population where an excess amount of adipose tissue exists, insulin is the only reliable biomarker to differentiate MS status. We surmise that differences in hs-CRP, leptin, and adiponectin are a reflection of their measurements in individuals with statistically different amounts of adipose tissue.

Weight cycling in a very low-calorie diet programme has no effect on weight loss velocity, blood pressure and serum lipid profile

Background:  Many dieters lose and regain weight many times. It is unclear whether weight cycling is associated with adverse metabolic alterations or becomes more difficult with each attempt.

Body Weight Loss with Phentermine Alone Versus Phentermine and Fenfluramine with Very-Low- Calorie Diet in an Outpatient Obesity Management Program: A Retrospective Study

BACKGROUND Obesity, which is epidemic in the United States, is associated with increased morbidity and mortality. The combination of diet, exercise, and a behavior-modification program often does not result in ideal body weight. OBJECTIVE The aim of this study was to determine the efficacy of phentermine (Phen) alone compared with phentermine plus fenfluramine (Phen-Fen), when used in combination with a very-low-calorie diet (VLCD) for weight loss in an outpatient obesity center. METHODS We analyzed data collected at the UCLA outpatient University Obesity Center between 1993 and 1999. Data for patients who attended the center for at least 12 weeks and at least 4 visits, who were taking Phen or Phen-Fen, and whose body mass index (BMI) was ≥30 kg/m(2) were included in this retrospective study. RESULTS During the study period, 3200 visits were recorded. Of 1133 potential participants, 446 patients were included in the analysis (309 women, 137 men; mean [SD] age, 46.7 [11.4] years; mean [SEM] body weight, 109.6 [26.7] kg; mean [SEM] BMI, 38.0 [7.6] kg/m(2)). Of these, 128 women and 60 men (mean [SEM] body weight at baseline, 103.4 [24.0] kg and 124.9 [28.2] kg, respectively) received Phen alone; 181 women and 77 men (mean [SEM] body weight at baseline, 102.5 [21.4] kg and 124.9 [30.2] kg, respectively) received Phen-Fen. No statistically significant differences were found between the Phen and Phen-Fen groups in mean age, body weight, or BMI for women or men at baseline. No significant differences in the time of weight loss were found when a VLCD was used with Phen alone compared with the Phen-Fen combination for either sex even at 12 weeks. For women, the mean total body weight loss was 7.4% in the Phen group and 8.7% in the Phen-Fen group, but these differences were not significant. For men, the mean total body weight loss was 7.8% in the Phen group and 8.2% in the Phen-Fen group, but these differences were not significant. No significant differences in BMI, severe adverse events, or dropout rate were found between the 2 treatment groups for men or women. CONCLUSIONS This outpatient study did not detect any significant difference between adjunctive uses of Phen compared with Phen-Fen pharmacotherapy when used with VLCD over 12 weeks. Phen can be used to achieve significant weight loss when combined with VLCD. The tolerability and positive physical response further suggest that Phen is a valuable medication for obesity management in the outpatient setting.

Naltrexone/Bupropion extended release-induced weight loss is independent of nausea in subjects without diabetes

Naltrexone/bupropion extended release (NB) is indicated as an adjunct to a reduced‐calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index of ≥30 or ≥27 kg m−2 and ≥1 weight‐related comorbidity (e.g. hypertension, type 2 diabetes and dyslipidaemia). In phase 3 clinical studies, nausea occurred in significantly higher proportions of subjects randomized to NB vs. placebo (PBO). In this pooled analysis of three phase 3, 56‐week, PBO‐controlled studies, we characterized nausea and weight loss in NB‐ and PBO‐treated subjects without diabetes. Subjects receiving NB (n = 1778) lost significantly more weight than those receiving PBO (n = 1160). Weight change was not significantly different between subjects reporting and not reporting nausea in either treatment arm. Severity of nausea was mild to moderate in ≥95% of all cases. In the NB arm, the highest incidence of nausea onset (9%) was reported during week 1. The median duration of mild, moderate and severe nausea in subjects receiving NB was 14, 9 and 13 days, respectively. Our results demonstrate that nausea associated with NB is rarely severe, primarily occurs early in treatment and is not a contributor to weight loss.