肥胖与慢性炎症的研究进展

肥胖常伴随着一系列代谢综合征的发生,肥胖引起的慢性炎症因为与各种代谢综合征的密切联系而成为目前的研究热点。慢性炎症的发生很复杂,涉及多个组织、器官和系统,并且炎症的发生会反过来影响组织的功能。目前针对慢性炎症发生机制的研究结果显示脂肪因子和免疫系统、内质网应激、细胞自噬作用以及内毒素的作用等形成的信号网络参与了慢性炎症的触发和发展。本文就慢性炎症与肥胖关联的几种可能发生机制的最新研究进展作一简要综述。     

Endothelial Dysfunction and Specific Inflammation in Obesity Hypoventilation Syndrome

Background

Obesity hypoventilation syndrome (OHS) is associated with increased cardiovascular morbidity. What moderate chronic hypoventilation adds to obesity on systemic inflammation and endothelial dysfunction remains unknown.

Question

To compare inflammatory status and endothelial function in OHS versus eucapnic obese patients.

Methodology

14 OHS and 39 eucapnic obese patients matched for BMI and age were compared. Diurnal blood gazes, overnight polysomnography and endothelial function, measured by reactive hyperemia peripheral arterial tonometry (RH-PAT), were assessed. Inflammatory (Leptin, RANTES, MCP-1, IL-6, IL-8, TNFα, Resistin) and anti-inflammatory (adiponectin, IL-1Ra) cytokines were measured by multiplex beads immunoassays.

Principal Findings

OHS exhibited a higher PaCO₂, a lower forced vital capacity (FVC) and tended to have a lower PaO₂ than eucapnic obese patients. _HS-CRP, RANTES levels and glycated haemoglobin (HbA1c) were significantly increased in OHS (respectively 11.1±10.9 vs. 5.7±5.5 mg.l⁻¹ for _HS-CRP, 55.9±55.3 vs 23.3±15.8 ng/ml for RANTES and 7.3±4.3 vs 6.1±1.7 for HbA1c). Serum adiponectin was reduced in OHS (7606±2977 vs 13660±7854 ng/ml). Endothelial function was significantly more impaired in OHS (RH-PAT index: 0.22±0.06 vs 0.51±0.11).

Conclusions

Compared to eucapnic obesity, OHS is associated with a specific increase in the pro-atherosclerotic RANTES chemokine, a decrease in the anti-inflammatory adipokine adiponectin and impaired endothelial function. These three conditions are known to be strongly associated with an increased cardiovascular risk.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00603096","term_id":"NCT00603096"}}NCT00603096     

Obesity Induced by Neonatal Overfeeding Worsens Airway Hyperresponsiveness and Inflammation

Background

Obesity is a risk factor for the development of certain respiratory diseases, and neonatal overfeeding results in an early onset of obesity in adulthood. However, the influence of neonatal overfeeding on respiratory diseases has rarely been studied. Therefore, this paper is aimed at investigating the effect of neonatal overfeeding on airway responsiveness and inflammation.

Methodology/Principal Findings

The neonatal overfeeding was induced by reducing litter size to three pups per litter (small litter, SL) in contrast to the normal litter size with ten pups per litter (NL) on postnatal day 3 (P3) in male ICR mice. On P21, mice were weaned to standard chow diet. Airway responsiveness to methacholine was measured either on P21 or P150. Total and classified inflammatory cells in bronchoalveolar lavage fluid (BALF) were counted, lung inflammatory cells were evaluated through staining with hematoxylin & eosin and F4/80 immunohistochemistry; lung fibrosis was evaluated through staining with Masson and α-SAM immunohistochemistry. Leptin levels in serum were measured by RIA; TNF-α levels in serum and BALF were quantified by ELISA; mRNA levels of TNF-α, CTGF and TGF-β1 in lung tissues were measured using real-time PCR. Mice from SL exhibited accelerated body weight gain, impaired glucose tolerance and hyperleptinemia. Enhanced airway responsiveness to methacholine was observed in SL mice on P150, but not on P21. Pulmonary inflammation was evident in SL mice on P150, as reflected by inflammatory cells especially macrophages around bronchi and interstitium. BALF and serum TNF-α levels and lung TNF-α mRNA expression were significantly increased in SL mice on P150. More collagen accumulated surrounding the bronchi on P150; lung mRNA levels of TGF-β1 and CTGF were also increased on P150.

Conclusion

In addition to inducing a variety of metabolic defects, neonatal overfeeding enhanced lung inflammation, which may lead to airway remodeling and airway hyperresponsiveness in adulthood.     

Inflammation in Response to n3 Fatty Acids in a Porcine Obesity Model

Fatty acids have distinct cellular effects related to inflammation and insulin sensitivity. Dietary saturated fat activates toll-like receptor 4, which in turn can lead to chronic inflammation, insulin resistance, and adipose tissue macrophage infiltration. Conversely, n3 fatty acids are generally antiinflammatory and promote insulin sensitivity, in part via peroxisome proliferator-activated receptor γ. Ossabaw swine are a useful biomedical model of obesity. We fed Ossabaw pigs either a low-fat control diet or a diet containing high-fat palm oil with or without additional n3 fatty acids for 30 wk to investigate the effect of saturated fats and n3 fatty acids on obesity-linked inflammatory markers. The diet did not influence the inflammatory markers C-reactive protein, TNFα, IL6, or IL12. In addition, n3 fatty acids attenuated the increase in inflammatory adipose tissue CD16^–CD14⁺ macrophages induced by high palm oil. High-fat diets with and without n3 fatty acids both induced hyperglycemia without hyperinsulinemia. The high-fat only group but not the high-fat group with n3 fatty acids showed reduced insulin sensitivity in response to insulin challenge. This effect was not mediated by decreased phosphorylation of protein kinase B. Therefore, in obese Ossabaw swine, n3 fatty acids partially attenuate insulin resistance but only marginally change inflammatory status and macrophage phenotype in adipose tissue.Abbreviations: AMPKα, AMP-activated protein kinase α, CRP, C-reactive protein, DHA, docosahexanoic acid, EPA, eicosapentanoic acid, HFP, high-fat palm-oil diet, HFPn3, high-fat palm-oil diet supplemented with n3 fatty acids, HOMA-IR, homeostasis model of assessment–, insulin resistance, LFC, low-fat control diet, PKB, protein kinase B, PUFA, polyunsaturated fatty acidsObesity is accompanied by chronic inflammation in adipose tissue; increased circulating concentrations of TNFα, IL6, and C-reactive protein (CRP); and decreased concentrations of adiponectin.² This chronic inflammation links obesity and the development of insulin resistance.³⁹ Dietary saturated fatty acids promote obesity in part through the induction of inflammation via activation of toll-like receptor 4 (the innate immune receptor for LPS).²⁸ The absence of functional tlr4 in mice reduces circulating proinflammatory cytokine concentrations and decreases macrophage infiltration into adipose tissue during high-fat diet-induced obesity.^8,28,32 Furthermore, in 3T3 L1 mouse adipocytes, palmitate activates NFκB, protein kinase C, and mitogen-activated protein kinase, all of which increase the production of inflammatory cytokines.¹For people who consume a diet high in saturated fat, a major determinant of health is the ratio of omega-6 to omega-3 fatty acids (that is, n6:n3) that is consumed.^5,6 Unlike saturated fatty acids, the n3 polyunsaturated fatty acids (PUFA) eicosapentanoic acid (EPA) and docosahexanoic acid (DHA) exert predominantly antiinflammatory effects, as is evident in that DHA antagonizes NFκB activation by palmitate in 3T3 L1 adipocytes.¹ In mice, EPA prevents or reverses hyperinsulinemia, hyperglycemia, and increased circulating monocyte chemotatic protein 1¹⁶ and decreases infiltration of adipose tissue with macrophages.³⁰ Moreover, n3 PUFA alleviate the decline in serum adiponectin that is associated with obesity,^12,15,30 and EPA decreases serum CRP in diabetic patients.²⁶Physiologic differences between rodents and humans underscore the need for comparative models in biomedical research, and the pig is emerging rapidly as a model for studies of energy metabolism and obesity. Like humans, pigs are natural omnivores, rely on apolipoprotein B100 to shuttle cholesterol in the LDL fraction, and have minimal brown fat retention postnatally. Furthermore, adipose depots in pigs are of sufficient size that multiple assays can be done on adipocytes or stromal vascular cells without pooling across depots or animals. Although Ossabaw swine have been used as models for metabolic syndrome, cardiovascular disease, coronary artery disease, and steatohepatisis,^11,20,24 little is known about adipose inflammation in these animals. Consequently, we sought to characterize obesity-linked inflammatory markers in the adipose tissue of this novel model and to test the hypothesis that adding n3 PUFA to a diet high in saturated fat attenuates chronic inflammation, protects against diet-induced insulin resistance, and alters phenotypic changes in adipose tissue macrophages.     

Deficiency of Interleukin-15 Confers Resistance to Obesity by Diminishing Inflammation and Enhancing the Thermogenic Function of Adipose Tissues

ObjectiveIL-15 is an inflammatory cytokine secreted by many cell types. IL-15 is also produced during physical exercise by skeletal muscle and has been reported to reduce weight gain in mice. Contrarily, our findings on IL-15 knockout (KO) mice indicate that IL-15 promotes obesity. The aim of this study is to investigate the mechanisms underlying the pro-obesity role of IL-15 in adipose tissues.MethodsControl and IL-15 KO mice were maintained on high fat diet (HFD) or normal control diet. After 16 weeks, body weight, adipose tissue and skeletal mass, serum lipid levels and gene/protein expression in the adipose tissues were evaluated. The effect of IL-15 on thermogenesis and oxygen consumption was also studied in primary cultures of adipocytes differentiated from mouse preadipocyte and human stem cells.ResultsOur results show that IL-15 deficiency prevents diet-induced weight gain and accumulation of lipids in visceral and subcutaneous white and brown adipose tissues. Gene expression analysis also revealed elevated expression of genes associated with adaptive thermogenesis in the brown and subcutaneous adipose tissues of IL-15 KO mice. Accordingly, oxygen consumption was increased in the brown adipocytes from IL-15 KO mice. In addition, IL-15 KO mice showed decreased expression of pro-inflammatory mediators in their adipose tissues.ConclusionsAbsence of IL-15 results in decreased accumulation of fat in the white adipose tissues and increased lipid utilization via adaptive thermogenesis. IL-15 also promotes inflammation in adipose tissues that could sustain chronic inflammation leading to obesity-associated metabolic syndrome.     

炎症与肿瘤的关系研究进展

炎症与肿瘤关系密切,慢性炎症与1/4以上癌症发生相关.炎症微环境中细胞因子,自由基,前列腺素,生长因子等炎性应答介质能诱导DNA甲基化,抑癌基因点突变和翻译后修饰等基因和表观学变化,引起维持正常细胞内环境稳定关健通路的改变并导致癌症的发生和演进;近年来,对炎症中microRNA和免疫应答相互作用的研究进一步加深了人们对炎症与肿瘤相关性的了解.本文就炎症与肿瘤的间的桥梁分子予以综述,鉴定这些关键细胞成分及相互通路特异性的改变能为炎症相关性肿瘤的早期诊断、预防和治疗提供分子靶标.     

Location of Airway Inflammation in Asthma and the Relationship to Orcadian Change in Lung Function

Nocturnal asthma is an important part of asthma as the majority of patients with asthma have nocturnal worsening in lung function. The etiology of this process is multifactorial and interactive. There are many naturally occurring circadian rhythms, which for the normal individual have only a minor effect on lung function. However, in the asthmatic patient, these day-to-night alterations produce increased airway inflammation and worsening of asthma. Although asthma is considered an airway disease, the location of the inflammatory response may be greater in the alveolar tissue area. If correct, this could alter the therapeutic approach to this disease.     

Psychiatric III-Health of Women and Its Relationship to Obesity and Body Fat Distribution

Objective : Abdominal obesity is associated with serious, prevalent diseases. Previously, psychiatric symptoms and ill-health has been found in this condition in men. The results of a similar study in women is reported herein. Research Methods and Procedures : A cohort of 1464 women, aged 40 years and recruited by systematic sampling, was examined (77.7% participation rate). Items regarding use of anxiolytics, hypnotics, and antidepressive drugs were registered, as well as symptoms of dyspepsia, sleeping disturbances, melancholy, and degree of life satisfaction. Smoking and alcohol consumption, as well as self-measured weight, height, waist, and hip circumferences, were reported, from which body mass index [BMI; weight (kg)/height² (m²), kg/m²] and the waist/hip circumference ratio (WHR) were calculated. Results : In bivariate analyses, BMI was associated with use of anxiolytics, antidepressive drugs, various sleeping disturbances, and a low degree of life satisfaction. After controlling for “the WHR, alcohol, and tobacco use in multivariate analysis, the associations between BMI and use of anxiolytics and sleeping disturbances remained significant. The WHR correlated with dyspepsia, sleeping problems, and use of antidepressive drugs. After adjustments for BMI, smoking, and alcohol, the relationship to dyspepsia and antidepressants remained significant. Discussion : The results suggest that elevated BMI (obesity) and elevated WHR (central fat distribution) are associated in different ways with symptoms of psychiatric ill-health in women. Obesity alone shows no such relationships to psy chiatric ill-health in men, whereas central fat distribution shows independent associations to all of the measured variables studied in this report in women, suggesting gender differences in these associations.     

Polymorphisms in Endothelin System Genes,Arsenic Levels and Obesity Risk

Background/Objectives

Obesity has been linked to morbidity and mortality through increased risk for many chronic diseases. Endothelin (EDN) system has been related to endothelial function but it can be involved in lipid metabolism regulation: Receptor type A (EDNRA) activates lipolysis in adipocytes, the two endothelin receptors mediate arsenic-stimulated adipocyte dysfunction, and endothelin system can regulate adiposity by modulating adiponectin activity in different situations and, therefore, influence obesity development. The aim of the present study was to analyze if single nucleotide polymorphisms (SNPs) in the EDN system could be associated with human obesity.

Subjects/Methods

We analyzed two samples of general-population-based studies from two different regions of Spain: the VALCAR Study, 468 subjects from the area of Valencia, and the Hortega Study, 1502 subjects from the area of Valladolid. Eighteen SNPs throughout five genes were analyzed using SNPlex.

Results

We found associations for two polymorphisms of the EDNRB gene which codifies for EDN receptor type B. Genotypes AG and AA of the rs5351 were associated with a lower risk for obesity in the VALCAR sample (p=0.048, OR=0.63) and in the Hortega sample (p=0.001, OR=0.62). Moreover, in the rs3759475 polymorphism, genotypes CT and TT were also associated with lower risk for obesity in the Hortega sample (p=0.0037, OR=0.66) and in the VALCAR sample we found the same tendency (p=0.12, OR=0.70). Furthermore, upon studying the pooled population, we found a stronger association with obesity (p=0.0001, OR=0.61 and p=0.0008, OR=0.66 for rs5351 and rs3759475, respectively). Regarding plasma arsenic levels, we have found a positive association for the two SNPs studied with obesity risk in individuals with higher arsenic levels in plasma: rs5351 (p=0.0054, OR=0.51) and rs3759475 (p=0.009, OR=0.53)

Conclusions

Our results support the hypothesis that polymorphisms of the EDNRB gene may influence the susceptibility to obesity and can interact with plasma arsenic levels.     

Health-Related Quality of Life in Relation to Obesity Grade,Type 2 Diabetes,Metabolic Syndrome and Inflammation

Background

Health-related quality of life (HR-QoL) may be compromised in obese individuals, depending on the presence of other complications. The aim of this study is to assess the effect of obesity-related conditions on HR-QoL. These conditions are i) grade of obesity with and without type 2 diabetes (T2D), ii) metabolic syndrome (MetS), and iii) level of inflammation.

Methods

From the Dutch LifeLines Cohort Study we included 13,686 obese individuals, aged 18–80 years. HR-QoL was measured with the RAND 36-Item Health Survey which encompasses eight health domains. We calculated the percentage of obese individuals with poor HR-QoL, i.e. those scoring below the domain and sex specific cut-off value derived from the normal weight population. Logistic regression analysis was used to calculate the probability of having poor domain scores according to the conditions under study.

Results

Higher grades of obesity and the additional presence of T2D were associated with lower HR-QoL, particularly in the domains physical functioning (men: odds ratios (ORs) 1.48–11.34, P<0.005, and women: ORs 1.66–5.05, P<0.001) and general health (men: ORs 1.44–3.07, P<0.005, and women: ORs 1.36–3.73, P<0.001). A higher percentage of obese individuals with MetS had a poor HR-QoL than those without MetS. Furthermore, we observed a linear trend between inflammation and the percentage of obese individuals with poor scores on the HR-QoL domains. Individuals with MetS were more likely to have poor scores in the domains general health, vitality, social functioning and role limitations due to emotional problems. Obese women with increased inflammation levels were more likely to have poor scores on all domains except role limitations due to emotional problems and mental health.

Conclusions

The impact of obesity on an individual’s quality of life is enhanced by grade of obesity, T2D, MetS and inflammation and are mainly related to reduced physical health. The mental well-being is less often impaired.     

Metformin Attenuates the Exacerbation of the Allergic Eosinophilic Inflammation in High Fat-Diet-Induced Obesity in Mice

A positive relationship between obesity and asthma has been well documented. The AMP-activated protein kinase (AMPK) activator metformin reverses obesity-associated insulin resistance (IR) and inhibits different types of inflammatory responses. This study aimed to evaluate the effects of metformin on the exacerbation of allergic eosinophilic inflammation in obese mice. Male C57BL6/J mice were fed for 10 weeks with high-fat diet (HFD) to induce obesity. The cell infiltration and inflammatory markers in bronchoalveolar lavage (BAL) fluid and lung tissue were evaluated at 48 h after ovalbumin (OVA) challenge. HFD obese mice displayed peripheral IR that was fully reversed by metformin (300 mg/kg/day, two weeks). OVA-challenge resulted in higher influx of total cell and eosinophils in lung tissue of obese mice compared with lean group. As opposed, the cell number in BAL fluid of obese mice was reduced compared with lean group. Metformin significantly reduced the tissue eosinophil infiltration and prevented the reduction of cell counts in BAL fluid. In obese mice, greater levels of eotaxin, TNF-α and NOx, together with increased iNOS protein expression were observed, all of which were normalized by metformin. In addition, metformin nearly abrogated the binding of NF-κB subunit p65 to the iNOS promoter gene in lung tissue of obese mice. Lower levels of phosphorylated AMPK and its downstream target acetyl CoA carboxylase (ACC) were found in lung tissue of obese mice, which were restored by metformin. In separate experiments, the selective iNOS inhibitor aminoguanidine (20 mg/kg, 3 weeks) and the anti-TNF-α mAb (2 mg/kg) significantly attenuated the aggravation of eosinophilic inflammation in obese mice. In conclusion, metformin inhibits the TNF-α-induced inflammatory signaling and NF-κB-mediated iNOS expression in lung tissue of obese mice. Metformin may be a good pharmacological strategy to control the asthma exacerbation in obese individuals.     

GPR105 Ablation Prevents Inflammation and Improves Insulin Sensitivity in Mice with Diet-Induced Obesity

GPR105, a G protein-coupled receptor for UDP-glucose, is highly expressed in several human tissues and participates in the innate immune response. Because inflammation has been implicated as a key initial trigger for type 2 diabetes, we hypothesized that GPR105 (official gene name: P2RY14) might play a role in the initiation of inflammation and insulin resistance in obesity. To this end, we investigated glucose metabolism in GPR105 knockout (KO) and wild-type (WT) mice fed a high-fat diet (HFD). We also examined whether GPR105 regulates macrophage recruitment to liver or adipose tissues by in vivo monocyte tracking and in vitro chemotaxis experiments, followed by transplantation of bone marrow from either KO or WT donors to WT recipients. Our data show that genetic deletion of GPR105 confers protection against HFD-induced insulin resistance, with reduced macrophage infiltration and inflammation in liver, and increased insulin-stimulated Akt phosphorylation in liver, muscle, and adipose tissue. By tracking monocytes from either KO or WT donors, we found that fewer KO monocytes were recruited to the liver of WT recipients. Furthermore, we observed that uridine 5-diphosphoglucose enhanced the in vitro migration of bone marrow-derived macrophages from WT but not KO mice, and that plasma uridine 5-diphosphoglucose levels were significantly higher in obese versus lean mice. Finally, we confirmed that insulin sensitivity improved in HFD mice with a myeloid cell-specific deletion of GPR105. These studies indicate that GPR105 ablation mitigates HFD-induced insulin resistance by inhibiting macrophage recruitment and tissue inflammation. Hence GPR105 provides a novel link between innate immunity and metabolism.     

The Relationship of Omental and Subcutaneous Adipocyte Size to Metabolic Disease in Severe Obesity

Objective

Several studies have reported the existence of a subgroup of obese individuals with normal metabolic profiles. It remains unclear what factors are responsible for this phenomenon. We proposed that adipocyte size might be a key factor in the protection of metabolically healthy obese (MHO) individuals from the adverse effects of obesity.

Subjects

Thirty-five patients undergoing bariatric surgery were classified as MHO (n = 15) or metabolically unhealthy obese (MUO, n = 20) according to cut-off points adapted from the International Diabetes Federation definition of the metabolic syndrome. Median body mass index (BMI) was 48 (range 40–71).

Results

There was a moderate correlation between omental adipocyte size and subcutaneous adipocyte size (r = 0.59, p<0.05). The MHO group had significantly lower mean omental adipocyte size (80.9±10.9 µm) when compared with metabolically unhealthy patients (100.0±7.6 µm, p<0.0001). Mean subcutaneous adipocyte size was similar between the two groups (104.1±8.5 µm versus 107.9±7.1 µm). Omental, but not subcutaneous adipocyte size, correlated with the degree of insulin resistance as measured by HOMA-IR (r = 0.73, p<0.0005), as well as other metabolic parameters including triglyceride/HDL-cholesterol ratio and HbA1c. Twenty-eight patients consented to liver biopsy. Of these, 46% had steatohepatitis and fibrosis. Fifty percent (including all the MHO patients) had steatosis only. Both omental and subcutaneous adipocyte size were significantly associated with the degree of steatosis (r = 0.66, p<0.0001 and r = 0.63, p<0.005 respectively). However, only omental adipocyte size was an independent predictor of the presence or absence of fibrosis.

Conclusion

Metabolically healthy individuals are a distinct subgroup of the severely obese. Both subcutaneous and omental adipocyte size correlated positively with the degree of fatty liver, but only omental adipocyte size was related to metabolic health, and possibly progression from hepatic steatosis to fibrosis.     

High Fat Diet-Induced Gut Microbiota Exacerbates Inflammation and Obesity in Mice via the TLR4 Signaling Pathway

Background & Aims

While it is widely accepted that obesity is associated with low-grade systemic inflammation, the molecular origin of the inflammation remains unknown. Here, we investigated the effect of endotoxin-induced inflammation via TLR4 signaling pathway at both systemic and intestinal levels in response to a high-fat diet.

Methods

C57BL/6J and TLR4-deficient C57BL/10ScNJ mice were maintained on a low-fat (10 kcal % fat) diet (LFD) or a high–fat (60 kcal % fat) diet (HFD) for 8 weeks.

Results

HFD induced macrophage infiltration and inflammation in the adipose tissue, as well as an increase in the circulating proinflammatory cytokines. HFD increased both plasma and fecal endotoxin levels and resulted in dysregulation of the gut microbiota by increasing the Firmicutes to Bacteriodetes ratio. HFD induced the growth of Enterobecteriaceae and the production of endotoxin in vitro. Furthermore, HFD induced colonic inflammation, including the increased expression of proinflammatory cytokines, the induction of Toll-like receptor 4 (TLR4), iNOS, COX-2, and the activation of NF-κB in the colon. HFD reduced the expression of tight junction-associated proteins claudin-1 and occludin in the colon. HFD mice demonstrated higher levels of Akt and FOXO3 phosphorylation in the colon compared to the LFD mice. While the body weight of HFD-fed mice was significantly increased in both TLR4-deficient and wild type mice, the epididymal fat weight and plasma endotoxin level of HFD-fed TLR4-deficient mice were 69% and 18% of HFD-fed wild type mice, respectively. Furthermore, HFD did not increase the proinflammatory cytokine levels in TLR4-deficient mice.

Conclusions

HFD induces inflammation by increasing endotoxin levels in the intestinal lumen as well as in the plasma by altering the gut microbiota composition and increasing its intestinal permeability through the induction of TLR4, thereby accelerating obesity.     

Relationship of Co-Morbidities of Obesity to Weight Loss and Four-Year Weight Maintenance/Rebound

This study examined the effect of weight loss (separate from energy restriction) and weight maintenance/rebound over time on blood pressure, serum lipids, and body composition in 24 obese (mean 137% ideal body weight (IEW)) females with mild to moderate hypertension. Weight loss was induced under tightly controlled General Clinical Research Center conditions until each subject had lost at least 10 kg (mean 13 kg) and attained normal body weight (<120% IBW). After 4 years subjects returned for repeat evaluation. Weight changes were compared with 24 pair-matched normal weight controls who were also followed for 4 years. With weight loss, significant improvements were seen in standing mean arterial pressure (MAP), serum total cholesterol, low-density lipoprotein cholesterol, and triglycerides. Subjects regained 11 kg (87% of the weight lost) over the 4 year follow-up period while control subjects gained only 2 kg. Subjects who chose self-selected exercise gained less weight than nonexercisers (6 kg vs. 13 kg, P<0.05). With weight regain there were significant increases in standing and supine MAP, total cholesterol, and high-density lipoprotein (HDL) cholesterol. The amount of weight regained was significantly correlated with standing MAP (r=0.73), triglycerides (r=0.43), and HDL cholesterol (r=-0.47). The percentage fat of the weight regained was no greater than that of the weight previously lost. Weight loss, distinct from energy restriction, was associated with improvements in blood pressure and serum lipid levels. The ability to sustain these improvements in the co-morbidities of obesity was directly related to the persistence and magnitude of weight loss maintenance.