Irisin as a Novel Biomarker of Subclinical Atherosclerosis in Severe Obesity.

Severe obesity (SO) can accelerate atherosclerosis and the onset of acute cardiovascular events. The diagnosis of atherosclerosis in the context of a high body mass index (BMI) can be challenging, making the identification of biomarkers clinically relevant. We aimed to assess the usefulness of irisin as a biomarker for subclinical atherosclerosis in participants with SO. This prospective observational study included 61 participants undergoing bariatric surgery for SO, defined as a BMI >40 kg/m2 or >35 kg/m2 with at least one comorbidity. Atherosclerotic plaques were detected by ultrasound. Plasma samples were obtained 1 month before and at 6 and 12 months after bariatric surgery to measure irisin by ELISA. Additionally, subcutaneous samples of adipose tissue were taken and genotyped to identify irisin polymorphism rs3480. Irisin levels were positively correlated with BMI (r = 0.23, p = 0.0064), negatively correlated with atheroma-related parameters (e.g., carotid intima-media thickness), and lower in subjects with atheroma (p < 0.0002). Irisin also showed good overall accuracy for discriminating plaque presence (AUC, 0.81; 95% CI, 0.6956-0.9156). However, the rs3480 polymorphism correlated with neither the irisin levels nor the presence of atheromas. Iirisin could identify subclinical atherosclerosis in SO and might facilitate clinical diagnosis.

Bariatric surgery decreases oxidative stress and protein glycosylation in patients with morbid obesity.

BACKGROUND: There is growing evidence that oxidative stress (OS) is a critical factor linking obesity with its associated comorbidities, such as cardiovascular diseases. AIM: To evaluate the degree of OS in people with morbid obesity and its relationship with glycoproteins, determined using 1H-NMR spectroscopy, before and after bariatric surgery (BS). METHODS: In this observational cohort study, plasma from 24 patients with BMI ≥ 40 kg/m2 (age: 21-65 years) was used to measure metabolites implicated in OS. We measured glycoprotein (GlycA, GlycB and GlycF) areas and shape factors (H/W = height/width). RESULTS: One year after BS, oxidized low-density lipoprotein had decreased by 49% (P < .0001), malondialdehyde by 32% (P = .0019) and lipoprotein (a) by 21% (P = .0039). The antioxidant enzymes paraoxonase-1 and catalase increased after BS (43%, P < .0001 and 54%, P = .0002, respectively). Superoxide dismutase-2 had fallen 1 year after BS (32%, P = .0052). After BS, both the glycoprotein areas and shape factors decreased by 20%-26%. These glycoproteins were significantly correlated with OS parameters. The plasma atherogenic index was 63% higher in obese individuals than 1 year after BS and correlated positively with glycoproteins. CONCLUSION: For the first time, we here demonstrate the relationship between OS parameters and glycoproteins in people with morbid obesity. So glycoproteins could therefore be a good indicator, together with the oxidative state to assess patient prognosis after BS.

Diet change affects intestinal microbiota restoration and improves vertical sleeve gastrectomy outcome in diet-induced obese rats.

PURPOSE: Obesity, a worldwide health problem, is linked to an abnormal gut microbiota and is currently most effectively treated by bariatric surgery. Our aim was to characterize the microbiota of high-fat fed Sprague-Dawley rats when subjected to bariatric surgery (i.e., vertical sleeve gastrectomy) and posterior refeeding with either a high-fat or control diet. We hypothesized that bariatric surgery followed by the control diet was more effective in reverting the microbiota modifications caused by the high-fat diet when compared to either of the two factors alone. METHODS: Using next-generation sequencing of ribosomal RNA amplicons, we analyzed and compared the composition of the cecal microbiota after vertical sleeve gastrectomy with control groups representing non-operated rats, control fed, high-fat fed, and post-operative diet-switched animals. Rats were fed either a high-fat or control low-fat diet and were separated into three comparison groups after eight weeks comprising no surgery, sham surgery, and vertical sleeve gastrectomy. Half of the rats were then moved from the HFD to the control diet. Using next-generation sequencing of ribosomal RNA amplicons, we analyzed the composition of the cecal microbiota of rats allocated to the vertical sleeve gastrectomy group and compared it to that of the non-surgical, control fed, high-fat fed, and post-operative diet-switched groups. Additionally, we correlated different biological parameters with the genera exhibiting the highest variation in abundance between the groups. RESULTS: The high-fat diet was the strongest driver of altered taxonomic composition, relative microbial abundance, and diversity in the cecum. These effects were partially reversed in the diet-switched cohort, especially when combined with sleeve gastrectomy, resulting in increased diversity and shifting relative abundances. Several highly-affected genera were correlated with obesity-related parameters. CONCLUSIONS: The dysbiotic state caused by high-fat diet was improved by the change to the lower fat, higher fiber control diet. Bariatric surgery contributed significantly and additively to the diet in restoring microbiome diversity and complexity. These results highlight the importance of dietary intervention following bariatric surgery for improved restoration of cecal diversity, as neither surgery nor change of diet alone had the same effects as when combined.

Expression, localization, and regulation of the neuregulin receptor ErbB3 in mouse heart.

Neuregulins (NRG) belong to the EGF family of growth factors, which are ligands of the ErbB receptors. Their expression in the adult heart is essential, especially when the heart is submitted to cardiotoxic stress such as that produced by anthracyclines. It is considered that ErbB4 is the only NRG receptor expressed by the adult heart. Upon binding, ErbB4 may dimerize with ErbB2 to generate signals inside cells. However, here we show the presence of ErbB3 in the mouse heart from birth to adulthood by Western blotting and real-time RT-PCR. The expression level of ErbB3 mRNA was lower than that of ErbB2 or ErbB4, but was more stable throughout postnatal development. In isolated heart myocytes, ErbB3 localized to the Z-lines similarly to ErbB1. Perfusion of isolated hearts with NRG-1ß induced phosphorylation of ErbB3, as well as ErbB2 and ErbB4. In adult mice, both ErbB2 and ErbB3, but not ErbB1 or ErbB4, were rapidly down-regulated upon the induction of heart hypertrophy. In conclusion, our results demonstrate that ErbB3, in addition to ErbB4, is a receptor for neuregulin-1ß in the adult mouse heart.

Effect of bariatric surgery on inflammation and endothelial dysfunction as processes underlying subclinical atherosclerosis in morbid obesity.

BACKGROUND: Inflammation and endothelial dysfunction are associated with morbid obesity (MO) and atherosclerosis. OBJECTIVE: To evaluate inflammation and endothelial function as the initial mechanisms underlying subclinical atherosclerosis in patients with MO, with and without atheromas, and their evolution after bariatric surgery (BS). SETTING: Arnau de Vilanova University Hospital and University of Barcelona. METHODS: Plasma samples from 66 patients with MO were obtained before BS and 6 and 12 months after BS. Patients were divided into 2 groups based on the presence of atheromatous plaques (detected by ultrasound imaging). RESULTS: Inflammation was increased as demonstrated by changes in the levels of fibroblast growth factor 21, adiponectin, leptin, interleukin 6, tumor growth factor α, nonesterified free fatty acids, lipoprotein(a) and C-reactive protein (CRP). Endothelial dysfunction was characterized by impaired angiogenesis (measured through angiopoietin 1 and 2 and brain-derived neurotrophic factor), vascular function (changes in endothelin 1 and thrombomodulin levels), and diapedesis (changes in intercellular and vascular cell adhesion molecules, and E- and P-selectins). Both mechanisms occurred regardless of the presence of atheromas. BS ameliorated both processes even in patients who already had subclinical atherosclerosis. However, CRP, thrombomodulin, and P-selectin levels were higher in patients with atheromas. CONCLUSIONS: Endothelial dysfunction and inflammation were detected before the appearance of structural changes in vessel walls on ultrasonography images. BS might prevent or slow atherogenesis in the early stages by breaking the vicious circle between inflammation and endothelial dysfunction. CRP, thrombomodulin, and P-selectin may have a critical role in plaque development and, together with the study of endothelial dysfunction, might be useful in assessing early atherosclerosis and its evolution after BS.

Effect of bariatric surgery in the evolution of oxidative stress depending on the presence of atheroma in patients with morbid obesity.

BACKGROUND: Morbid obesity is associated with accelerated atherosclerosis, a chronic vascular disease related to oxidative stress (OS) and endothelial dysfunction. OBJECTIVES: We aimed to evaluate the effect of bariatric surgery (BS) on oxidative stress as a cardiovascular risk factor in patients with and without atheromatous plaques. SETTING: Arnau de Vilanova University Hospital and University of Barcelona. METHODS: Plasma samples from 66 patients with morbid obesity were obtained before BS and 6 and 12 months after. Patients were divided into 2 groups based on the presence of atheromatous plaques (detected by ultrasonography). OS parameters were measured by enzyme-linked immunosorbent assay. RESULTS: Patients with morbid obesity had OS independently of the presence of an atheroma, but oxidized low-density lipoprotein levels were higher in patients with plaques throughout the study (P = .0430). After surgery, oxidized low-density lipoprotein and malondialdehyde levels decreased significantly (P < .0001 in both cases). At the beginning of the study, antioxidant enzyme levels were the same between the groups. After surgery, paraoxonase 1 levels were increased (P < .0001) in the group without plaque, being significantly higher (P = .0147). Superoxide dismutase 2 levels were only decreased in patients without plaque (P < .0010), while catalase activity was higher in patients with plaque. CONCLUSIONS: Morbid obesity may lead to chronic OS, which increases predisposition to atherogenesis. BS improves the antioxidant profile and reduces OS and co-morbidities in both groups. However, the benefits are greater for patients without plaque. Therefore, BS may prevent atheroma formation and also could prevent plaque rupture by decreasing OS.

Impact of bariatric surgery on subclinical atherosclerosis in patients with morbid obesity.

BACKGROUND: The main cause of death in obese individuals is cardiovascular disease precipitated by atherosclerosis. Endothelial dysfunction and inflammation are considered early events in the development of the disease. OBJECTIVES: The aim of this study was to identify biomarkers of subclinical atherosclerosis in patients with morbid obesity by comparing clinical, vascular, and biochemical parameters indicative of endothelial dysfunction in patients with and without atheromatous plaque and monitoring changes after bariatric surgery. SETTINGS: Multicenter collaboration between Biochemistry and Biomedicine Department in Barcelona University and University Hospital Arnau de Vilanova in Lleida. METHODS: Plasma samples from 66 patients with morbid obesity were obtained before bariatric surgery and at 6 and 12 months after. Patients were divided into 2 groups based on the presence of atheromatous plaque. We used contrast-enhanced carotid ultrasound, enzyme-linked immunosorbent assay, Griess, and EndoPAT-2000 methods. RESULTS: Patients with plaque showed the worst profile of cardiovascular risk factors. Carotid intima-media thickness and plasminogen activator inhibitor-1 were higher in plaque group (P < .0001). After bariatric surgery, vasa vasorum, oxidized low-density lipoprotein, and plasminogen activator inhibitor-1 decreased (P < .0001 in all cases). CONCLUSIONS: Obesity promotes atherogenesis, leading to vascular endothelial damage. Bariatric surgery reduces cardiovascular risk and the prognosis is better for patients without plaque. The increase in plasminogen activator inhibitor-1, carotid intima-media thickness, and vasa vasorum proliferation might be the first alterations in the atheromatous process in obesity and could serve as good biomarkers of subclinical atherosclerosis.

Increased expression and activity of hepatic lipase in the liver of morbidly obese adult patients in relation to lipid content.

BACKGROUND: The types and sources of lipid deposition in the liver of most patients with morbid obesity, as well as the effects of bariatric surgery, are discussed. METHODS: In 26 patients with morbid obesity who underwent bariatric surgery, we analyzed different kinds of lipids and hepatic lipase (HL) from both plasma and liver biopsies performed 12-18 months after surgery. RESULTS: The HL activity and HL-mRNA in morbidly obese (MO) livers were high (258 +/- 17 mU/g, and 4.5-fold, respectively); after surgery, the activity decreased (137 +/- 15 mU/g, p < 0.001) but not the levels of HL-mRNA (4.3-fold). Plasma HL activity was also high (4.31 +/- 0.94 mU/mL plasma), and it decreased during weight loss (2.01 +/- 0.29 mU/mL, p < 0.01); moreover, it correlated (r = 0.3694, p < 0.05) with decreased liver HL activity. Adrenocorticotropic hormone in MO was higher (27 +/- 3 pg/mL) than after surgery (13 +/- 1 pg/mL, p < 0.001). All hepatic and plasma lipids were significantly increased in MO patients, but, after bariatric surgery, most of those parameters recovered or normalized. Liver HL activity correlated with total and esterified cholesterol (r = 0.4399, p < 0.001 and r = 0.4395, p < 0.01, respectively). CONCLUSION: High HL in MO patients could allow for liver intake of cholesterol that could be re-exported to steroidogenic organs to synthesize steroidal hormones. A decrease of plasma HL during weight loss could be a good index for improvement of liver disease.

Lipoprotein lipase expression in livers of morbidly obese patients could be responsible for liver steatosis.

BACKGROUND: Most patients with morbid obesity develop non-alcoholic fatty liver disease (NAFLD). The origins of lipid deposition in the liver and the effects of bariatric surgery in the obese with NAFLD are controversial. METHODS: We analyzed lipids and lipoprotein lipase (LPL) in both plasma and liver biopsies performed before and 12-18 months after Roux-en-Y gastric bypass surgery in 26 patients. RESULTS: In the livers of morbidly obese patients, the levels of LPL messenger RNA (mRNA) were higher (4.5-fold) before surgery than afterwards than control livers. In these patients, LPL activity was also significantly higher (91 +/- 7 mU/g) than in controls (51 +/- 3 mU/g, p = 0.0026) and correlated with the severity of the liver damage. All hepatic lipids were significantly increased in obese patients; however, after bariatric surgery, these lipids, with the exception of NEFA, tended to recover to normal levels. CONCLUSIONS: The liver of obese patients presented higher LPL activity than controls, and unlike the controls, this enzyme could be synthesized in the liver because it also present LPL mRNA. The presence of the LPL activity could enable the liver to capture circulating triacylglycerides, thus favoring the typical steatosis observed in these patients.

Seasonal variation of body weight loss after bariatric surgery.

Seasonal variations have been described in humans in several variables such as sleep, mood, appetite, food preferences, or body weight. We hypothesized that these variations could also influence the decrease in body weight rate in patients submitted to body weight loss interventions. Thus, here we tested the variations of weight loss according to the time of the year the surgery took place in a group patients (n = 1322) submitted to bariatric surgery in the Hospital Universitari de la Vall d'Hebron in Barcelona (geographical coordinates: 41°25'41″N 2°8'32″E). For the analysis, the percentage of total body weight loss (%TWL), excess body weight loss (%EWL) and percentage of body mass index loss (%BMIL) were calculated at 3 (n = 1255), 6 (n = 1172), 9 (n = 1002), and 12 months (n = 1076) after surgery. For %EWL and %BMIL a statistically significant seasonal variation was detected when the variables were calculated at 3 months, but not at the other times, with more weight loss in summer-fall. However, seasonal variations were not detected for %TWL (p = 0.09). The mean amplitude of the seasonal rhythm for %EWL was of 1.8%, while for the rhythm of %BMIL was 0.7%. Moreover, a second peak was detected in January-February modulating the seasonal rhythm of the two variables. Results confirm seasonal variations in humans and indicate that short term responses to weight loss can be modulated by the time of year.

Seasonal variations of changes in lipid and glucidic variables after bariatric surgery.

Seasonality is a phenomenon that is characterized by changes over the year in sleep, mood, behaviour, appetite and body weight. In humans, seasonal variations have been found in certain variables, such as lipid variables and body mass index. We hypothesize that this rhythm could influence the expected variation of the levels of biochemical variables in cases of body weight loss. Thus, the goal of this study was to observe whether the time of year in which bariatric surgery (BS) took place modulated the changes in several variables related to glucidic and lipid metabolism. Blood samples were obtained from 24 women and 10 men before BS and 1 and 3 months after BS. We calculated the percentage of variation that occurred for each individual and for each variable as a function of the time of the year. Data were adjusted to a 12-month period sinusoidal curve, with significance being set at p < 0.05. The results showed that almost all of the studied variables changed due to the BS according to a seasonal rhythm. Most of the variables showed a decrease that was most prominent in winter. In the cases of body mass index (BMI), adrenocorticotropin hormone (ACTH), and cortisol, the highest variation occurred in winter. Insulin and cholesterol in high-density lipoproteins (cHLD) variations were higher in springtime. Glucose variation showed a decrease after surgery with acrophase in summer-fall and plasminogen activator inhibitor-1 (PAI-1) and homeostatic model assessment-insulin resistance (HOMA-IR) in spring-summer. Ghrelin levels showed increases with a rhythm of variation with an acrophase in summer-fall. The seasonal rhythm found in this study fits nearly with the inverse of the endogenous circannual rhythm of the variables studied. The time of the year when the highest variation takes place is related to the circannual rhythm of the variable. The results agree with the manifestation of seasonal rhythm in human biochemical variables, which are reflected in the responses to weight loss after BS.

Lipoprotein lipase (LPL) is highly expressed and active in the ovary of European sea bass (Dicentrarchus labrax L.), during gonadal development.

The oocytes of many fish species accumulate high amounts of neutral lipids as a caloric reserve for embryonic and larval development. We propose that lipoprotein lipase (LPL, EC 3.1.1.34) plays an important role in supplying the oocytes with fatty acids and we have cloned its cDNA from the ovary of sea bass, and determined the patterns of LPL activity and LPL mRNA expression in the ovary. The cDNA obtained was 3051 bp long with an open reading frame encoding 518 amino acids. The amino acid sequence has a high similarity and shows similar structural features to LPL of other species. Northern blot analysis revealed LPL expression in adipose tissue and gonads only. LPL activity and LPL mRNA expression in the ovary was very high in fish with a gonadosomatic index (GSI) above 5, coinciding with the appearance of a high number of lipid droplets in the ooplasm. The LPL mRNA expression was localised to the follicle cells surrounding the oocyte. Our results suggest that LPL is likely to play an important role in the incorporation of neutral lipids into the oocytes, and that follicle cells, in addition to participating in steroidogenesis, also may be important in building up oocyte lipid reserves.

Roux-en-Y gastric bypass, sleeve gastrectomy, or one anastomosis gastric bypass as rescue therapy after failed adjustable gastric banding: a multicenter comparative study.

BACKGROUND: To date, laparoscopic adjustable gastric banding remains the third most commonly performed surgical procedure for weight loss. Some patients fail to get acceptable outcomes and undergo revisional surgery at rates ranging from 7% to 60%. Roux-en-Y gastric bypass (RYGB), one anastomosis gastric bypass (OAGB), and sleeve gastrectomy (SG) are among the most common salvage options for failed laparoscopic adjustable gastric banding. OBJECTIVE: To compare the outcomes of converting failed laparoscopic adjustable gastric banding to RYGB, OAGB, or SG. METHODS: Data collected from 7 experienced bariatric centers around the world were retrospectively collected, reviewed, and analyzed. Final body mass index (BMI), change in BMI, percentage excess BMI loss, and major complications with particular attention to leaks, hemorrhage, and mortality were reported. RESULTS: Of 1219 patients analyzed, 74% underwent RYGB, 16% underwent OAGB, and 10% underwent SG after banding failure. The mean age was 38 years (±10 yr), and 82% of patients were women. The mean follow-up was 33 months. The follow-up rate was 100%, 87%, and 52% at 1, 3, and 5 years, respectively. At the latest follow-up, percentage excess BMI loss >50% was achieved by 75% of RYGB, 85% of OAGB, and 67% of SG patients. Postoperative complications occurred in 13% of patients after RYGB, 5% after OAGB, and 15% after SG. CONCLUSION: Our data show that it is possible to achieve or maintain significant weight loss with an acceptable complication rate with all 3 surgical options.

Diet Change After Sleeve Gastrectomy Is More Effective for Weight Loss Than Surgery Only.

BACKGROUND: Bariatric surgery with or without diet change has become one of the most effective treatments for obesity. The objective of this study was to observe the effects of vertical sleeve gastrectomy (VSG) and diet change in Sprague-Dawley rats on both body and tissue weights. METHODS: Eighteen rats were fed with a standard chow diet (SCD) (C group), and 36 rats were fed with a high-fat diet (HFD) (diet-induced obesity (DIO) group). After 8 weeks, the animals underwent VSG, sham surgery or no surgery (NS). After surgery, a third of the rats fed with the HFD changed to the SCD (DIO + C group). Body weight, food and energy intake were recorded daily during the experiment (12 weeks). Food efficiency (%) (FE) was determined from weekly weight gain and weekly kilocalorie consumed measurements. RESULTS: The DIO group had higher and significant weight gain than the C group at the time of surgery (p < 0.001). The major weight loss (WL) was observed in the DIO + C-VSG group, during the 4 weeks after surgery. Adipose tissues in the DIO + C-VSG group were drastically reduced and had a weight similar to those in the C-VSG group. CONCLUSION: VSG and the diet change combination led to a greater WL, which was maintained during the 4 weeks post-surgery, leading to a normalization of body weight. VSG and diet change also affected most of the tissues, not only adipose, showing a global change in whole body composition.

Seasonal variation in plasma lipids and lipases in young healthy humans.

Although intermediate metabolism is known to follow circadian rhythms, little information is available on the variation in lipase activities (lipoprotein and hepatic lipase, LPL and HL, respectively) and lipids throughout the year. In a cross-sectional study, we collected and analysed blood from 245 healthy students (110 men and 135 women) between 18 and 25 years old from the University of Barcelona throughout the annual campaign (March, May, October and December) of the blood bank. All subjects gave their written informed consent to participate. All blood samples were taken after breakfast at 8:00 and 11:00 am. Plasma glucose, total plasma protein, triacylglycerides (TAG), free fatty acids (FFA), free cholesterol and esterified cholesterol (FC and TC, respectively), cholesterol in low-density lipoproteins (cLDL), cholesterol in high-density lipoproteins (cHDL), phospholipids (PL) and lipase activities (LPL and HL) were determined. Cosinor analysis was used to evaluate the presence (significance of fit cosine curve to data and variance explained by rhythm) and characteristics of possible 12-month rhythms (acrophase, MESOR and amplitude). Statistically significant seasonal rhythms were detected for all the variables studied except proteins, with most of them peaking in the winter season. The lowest value for cLDL and the HL occurs in summer, while for cHDL and the LPL it is in winter. These findings demonstrate for the first time that in physiological conditions, plasma LPL and HL activities and lipids follow seasonal rhythms. The metabolic significance of this pattern is discussed.

LXR-dependent regulation of macrophage-specific reverse cholesterol transport is impaired in a model of genetic diabesity.

Diabesity and fatty liver have been associated with low levels of high-density lipoprotein cholesterol, and thus could impair macrophage-specific reverse cholesterol transport (m-RCT). Liver X receptor (LXR) plays a critical role in m-RCT. Abcg5/g8 sterol transporters, which are involved in cholesterol trafficking into bile, as well as other LXR targets, could be compromised in the livers of obese individuals. We aimed to determine m-RCT dynamics in a mouse model of diabesity, the db/db mice. These obese mice displayed a significant retention of macrophage-derived cholesterol in the liver and reduced fecal cholesterol elimination compared with nonobese mice. This was associated with a significant downregulation of the hepatic LXR targets, including Abcg5/g8. Pharmacologic induction of LXR promoted the delivery of total tracer output into feces in db/db mice, partly due to increased liver and small intestine Abcg5/Abcg8 gene expression. Notably, a favorable upregulation of the hepatic levels of ABCG5/G8 and NR1H3 was also observed postoperatively in morbidly obese patients, suggesting a similar LXR impairment in these patients. In conclusion, our data show that downregulation of the LXR axis impairs cholesterol transfer from macrophages to feces in db/db mice, whereas the induction of the LXR axis partly restores impaired m-RCT by elevating the liver and small intestine expressions of Abcg5/g8.

Defective thermoregulation, impaired lipid metabolism, but preserved adrenergic induction of gene expression in brown fat of mice lacking C/EBPbeta.

C/EBPbeta (CCAAT/enhancer-binding protein beta) is a transcriptional regulator of the UCP1 (uncoupling protein-1) gene, the specific marker gene of brown adipocytes that is responsible for their thermogenic capacity. To investigate the role of C/EBPbeta in brown fat, we studied the C/EBPbeta-null mice. When placed in the cold, C/EBPbeta(-/-) mice did not maintain body temperature. This cold-sensitive phenotype occurred, although UCP1 and PGC-1alpha (peroxisome-proliferator-activated receptor gamma co-activator-1alpha) gene expression was unaltered in brown fat of C/EBPbeta(-/-) mice. The UCP1 gene promoter was repressed by the truncated inhibitory C/EBPbeta isoform LIP (liver-enriched transcriptional inhibitory protein, the truncated inhibitory C/EBPbeta isoform). Since C/EBPbeta-null mice lack both C/EBPbeta isoforms, active LAP (liver-enriched transcriptional activatory protein, the active C/EBPbeta isoform) and LIP, the absence of LIP may have a stronger effect than the absence of LAP upon UCP1 gene expression. Gene expression for UCP2 and UCP3 was not impaired in all tissues analysed. In primary brown adipocytes from C/EBPbeta(-/-) mice, induction of gene expression by noradrenaline was preserved. In contrast, the expression of genes related to lipid storage was impaired, as was the amount of triacylglycerol mobilized after acute cold exposure in brown fat from C/EBPbeta(-/-) mice. LPL (lipoprotein lipase) activity was also impaired in brown fat, but not in other tissues of C/EBPbeta(-/-) mice. LPL protein levels were also diminished, but this effect was independent of changes in LPL mRNA, suggesting that C/EBPbeta is involved in the post-transcriptional regulation of LPL gene expression in brown fat. In summary, defective thermoregulation owing to the lack of C/EBPbeta is associated with the reduced capacity to supply fatty acids as fuels to sustain brown fat thermogenesis.

Diabetic and dyslipidaemic morbidly obese exhibit more liver alterations compared with healthy morbidly obese.

BACKGROUND & AIMS: To study the origin of fat excess in the livers of morbidly obese (MO) individuals, we analysed lipids and lipases in both plasma and liver and genes involved in lipid transport, or related with, in that organ. METHODS: Thirty-two MO patients were grouped according to the absence (healthy: DM - DL -) or presence of comorbidities (dyslipidemic: DM - DL +; or dyslipidemic with type 2 diabetes: DM + DL +) before and one year after gastric bypass. RESULTS: The livers of healthy, DL and DM patients contained more lipids (9.8, 9.5 and 13.7 times, respectively) than those of control subjects. The genes implicated in liver lipid uptake, including HL, LPL, VLDLr, and FAT/CD36, showed increased expression compared with the controls. The expression of genes involved in lipid-related processes outside of the liver, such as apoB, PPARα and PGC1α, CYP7a1 and HMGCR, was reduced in these patients compared with the controls. PAI1 and TNFα gene expression in the diabetic livers was increased compared with the other obese groups and control group. Increased steatosis and fibrosis were also noted in the MO individuals. CONCLUSIONS: Hepatic lipid parameters in MO patients change based on their comorbidities. The gene expression and lipid levels after bariatric surgery were less prominent in the diabetic patients. Lipid receptor overexpression could enable the liver to capture circulating lipids, thus favouring the steatosis typically observed in diabetic and dyslipidaemic MO individuals.

Changes in lipoprotein lipase modulate tissue energy supply during stress.

We studied the variations caused by stress in lipoprotein lipase (LPL) activity, LPL-mRNA, and local blood flow in LPL-rich tissues in the rat. Stress was produced by body immobilization (Immo): the rat's limbs were taped to metal mounts, and its head was placed in a plastic tube. Chronic stress (2 h daily of Immo) decreased total LPL activity in mesenteric and epididymal white adipose tissue (WAT) and was accompanied by a weight reduction of these tissues. In limb muscle, heart, and adrenals, total LPL activity and mRNA levels increased, and, in plasma, LPL activity and mass also increased. Acute stress (30-min Immo) caused a decrease in total LPL activity only in retroperitoneal WAT and an increase in preheparin plasma active LPL, but the overall weight of this tissue did not vary significantly. We propose an early release of the enzyme from this tissue into the bloodstream by some unknown extracellular pathways or other local mechanisms. These changes in this key energy-regulating enzyme are probably induced by catecholamines. They modify the flow of energy substrates between tissues, switching the WAT from importer to exporter of free fatty acids and favoring the uptake by muscle of circulating triacylglycerides for energy supply. Moreover, we found that acute stress almost doubled blood flow in all WAT studied, favoring the export of free fatty acids.

Hepatic and visceral adipose tissue 11ßHSD1 expressions are markers of body weight loss after bariatric surgery.

OBJECTIVE: Cortisolemia and 11ßHSD1 in liver and adipose tissue are altered in obesity. However, their participation in the development of obesity remains unclear. This study analyzed these parameters in the transition from morbid to type 1 obesity after bariatric surgery. METHODS: A group of 34 patients with morbid obesity and 22 nonobese subjects were recruited. Initial hypothalamus-pituitary-adrenal (HPA) basal activity and 11ßHSD1 mRNA expression in liver, subcutaneous (SAT), and visceral adipose tissue (VAT) were evaluated. A year after bariatric surgery (weight loss of 48 kg), these parameters were reappraised in plasma, SAT, and liver. RESULTS: Body weight loss was accompanied by a downshift in basal HPA activity and 11ßHSD1 expression in SAT. In patients with morbid obesity, 11ßHSD1 expression correlated positively with BMI in VAT and negatively in liver at 6 and 12 months after surgery. In SAT, a correlation was observed with body weight only when patients showed type 1 obesity. Insulin, glucose, and HOMA correlated positively with all the HPA indicators and 11ßHSD1 expression in SAT. CONCLUSIONS: Body weight loss after bariatric surgery is accompanied by a downshift in basal HPA activity. Hepatic and VAT 11ßHSD1 expressions in morbid obesity are predictors of body weight loss.