Adipocyte Proteins and Storage of Endogenous Fatty Acids in Visceral and Subcutaneous Adipose Tissue in Severe Obesity.

OBJECTIVE: This study tested whether substrate concentrations or fatty acid storage proteins predict storage of endogenous lipids in visceral adipose tissue (VAT) and upper body subcutaneous adipose tissue (UBSQ) fat. METHODS: The day prior to surgery, 25 patients undergoing bariatric procedures received an infusion of autologous [1-14 C]triolein-labeled very low-density lipoprotein (VLDL) particles, and during surgery, they received a continuous [U-13 C]palmitate infusion/bolus [9,10-3 H]palmitate tracer. VAT and UBSQ fat were collected to measure VLDL-triglyceride (TG) storage, direct free fatty acid (FFA) storage rates, CD36 content, lipoprotein lipase (LPL), acyl-CoA synthetase, diacylglycerol acetyl-transferase, and glycerol-3-phosphate acyltransferase activities. RESULTS: Storage of VLDL-TG and FFA-palmitate in UBSQ and VAT was not different. Plasma palmitate concentrations correlated with palmitate storage rates in UBSQ and VAT (r = 0.46, P = 0.02 and r = 0.46, P = 0.02, respectively). In VAT, VLDL-TG storage was correlated with VLDL concentrations (r = 0.53, P < 0.009) and LPL (r = 0.42, P < 0.05). In UBSQ, VLDL-TG storage was correlated with LPL (r = 0.42, P < 0.05). CD36, acyl-CoA synthetase, glycerol-3-phosphate acyltransferase, and diacylglycerol acetyl-transferase were not correlated with VLDL-TG or palmitate storage. CONCLUSIONS: Adipose storage of VLDL-TG is predicted by VLDL-TG concentrations and LPL; FFA concentrations predict direct adipose tissue FFA storage rates.

Hepatic Fatty Acid Balance and Hepatic Fat Content in Humans With Severe Obesity.

OBJECTIVE: Nonalcoholic fatty liver disease can lead to hepatic inflammation/damage. Understanding the physiological mechanisms that contribute to excess hepatic lipid accumulation may help identify effective treatments. DESIGN: We recruited 25 nondiabetic patients with severe obesity scheduled for bariatric surgery. To evaluate liver export of triglyceride fatty acids, we measured very-low-density lipoprotein (VLDL)-triglyceride secretion rates the day prior to surgery using an infusion of autologous [1-14C]triolein-labeled VLDL particles. Ketone body response to fasting and intrahepatic long-chain acylcarnitine concentrations were used as indices of hepatic fatty acid oxidation. We measured intraoperative hepatic uptake rates of plasma free fatty acids using a continuous infusion of [U-13C]palmitate, combined with a bolus dose of [9,10-3H]palmitate and carefully timed liver biopsies. Total intrahepatic lipids were measured in liver biopsy samples to determine fatty liver status. The hepatic concentrations and enrichment from [U-13C]palmitate in diacylglycerols, sphingolipids, and acyl-carnitines were measured using liquid chromatography/tandem mass spectrometry. RESULTS: Among study participants with fatty liver disease, intrahepatic lipid was negatively correlated with VLDL-triglyceride secretion rates (r = -0.92, P = 0.01) but unrelated to hepatic free fatty acid uptake or indices of hepatic fatty acid oxidation. VLDL-triglyceride secretion rates were positively correlated with hepatic concentrations of saturated diacylglycerol (r = 0.46, P = 0.02) and sphingosine-1-phosphate (r = 0.44, P = 0.03). CONCLUSION: We conclude that in nondiabetic humans with severe obesity, excess intrahepatic lipid is associated with limited export of triglyceride in VLDL particles rather than increased uptake of systemic free fatty acids.

Subcutaneous adipose tissue free fatty acid uptake measured using positron emission tomography and adipose biopsies in humans.

Positron emission tomography (PET) radiopharmaceuticals can noninvasively measure free fatty acid (FFA) uptake into adipose tissue. We studied 29 volunteers to test whether abdominal and femoral subcutaneous adipose tissue FFA uptake measured using [1-11C]palmitate PET agrees with FFA storage rates measured using an intravenous bolus of [1-14C]palmitate and adipose biopsies. The dynamic left ventricular cavity PET images combined with blood sample radioactivity corrected for the 11CO2 content were used to create the blood time activity curve (TAC), and the constant (Ki) was determined using Patlak analysis of the TACs generated for regions of interest in abdominal subcutaneous fat. These data were used to calculate palmitate uptake rates in abdominal subcutaneous adipose tissue (µmol·kg-1·min-1). Immediately after the dynamic imaging, a static image of the thigh was taken to measure the standardized uptake value (SUV) in thigh adipose tissue, which was scaled to each participant's abdominal adipose tissue SUV to calculate thigh adipose palmitate uptake rates. Abdominal adipose palmitate uptake using PET [1-11C]palmitate was correlated with, but significantly (P < 0.001) greater than, FFA storage measured using [1-14C]palmitate and adipose biopsy. Thigh adipose palmitate measured using PET calculation was positively correlated (R2 = 0.44, P < 0.0001) with and not different from the biopsy approach. The relative differences between PET measured abdominal subcutaneous adipose tissue palmitate uptake and biopsy-measured palmitate storage were positively correlated (P = 0.03) with abdominal subcutaneous fat. We conclude that abdominal adipose tissue FFA uptake measured using PET does not equate to adipose FFA storage measured using biopsy techniques.

Free fatty acid flux measured using [1-11C]palmitate positron emission tomography and [U-13C]palmitate in humans.

PET radiopharmaceuticals can noninvasively measure free fatty acid (FFA) tissue uptake. Investigators often use PET scan-derived data to calculate FFA flux. We tested whether the [1-11C]palmitate PET measures of palmitate flux provide results equivalent to a continuous infusion of [U-13C]palmitate. Nine volunteers participated in study 1 to evaluate whether a rapidly (10-20 s) given bolus of [1-11C]palmitate affects calculated flux results. Thirty volunteers participated in study 2, which was identical to study 1 except that the [1-11C]palmitate bolus was given over 1 min. Volunteers in both studies also received a continuous intravenous infusion of [U-13C]palmitate. Plasma palmitate concentrations and enrichment were measured by liquid chromatography-mass spectrometry. The PET/CT images were analyzed on a workstation running PMOD. Palmitate flux was estimated using PET time-activity curve (TAC) data from regions of interest in the left ventricle (LV) and aorta both with and without hybrid TACs that employed the 11CO2-corrected data for the first 5 min and the 11CO2-corrected blood radioactivity for the remainder of the PET scan. Palmitate flux in study 1 measured with PET [1-11C]palmitate and [U-13C]palmitate were not correlated, and the PET [1-11C]palmitate flux was significantly less than the [U-13C]palmitate measured flux. In study 2, the palmitate flux using PET [1-11C]palmitate hybrid LV models provided closer mean estimates of [U-13C]palmitate measured flux. The best PET calculation approaches predicted 64% of the interindividual variance in [U-13C]palmitate measured flux. Palmitate kinetics measured using [1-11C]palmitate/PET do not provide the same palmitate kinetic results as the continuous infusion [U-13C]palmitate approach.

Low Risk of Pneumonia From Pneumocystis jirovecii Infection in Patients With Inflammatory Bowel Disease Receiving Immune Suppression.

BACKGROUND & AIMS: Use of immunosuppressants and inflammatory bowel disease (IBD) may increase the risk of pneumonia caused by Pneumocystis jirovecii (PJP). We assessed the risk of PJP in a population-based cohort of patients with IBD treated with corticosteroids, immune-suppressive medications, and biologics. METHODS: We performed a population-based cohort study of residents of Olmsted County, Minnesota, diagnosed with Crohn's disease (n = 427) or ulcerative colitis (n = 510) from 1970 through 2011. Records of patients were reviewed to identify all episodes of immunosuppressive therapies and concomitant PJP prophylaxis through February 2016. We reviewed charts to identify cases of PJP, cross-referenced with the Rochester Epidemiology Project database (using diagnostic codes for PJP) and the Mayo Clinic and Olmsted Medical Center databases. The primary outcome was risk of PJP associated with the use of corticosteroids, immune-suppressive medications, and biologics by patients with IBD. RESULTS: Our analysis included 937 patients and 6066 patient-years of follow-up evaluation (median, 14.8 y per patient). Medications used included corticosteroids (520 patients; 55.5%; 555.4 patient-years of exposure), immunosuppressants (304 patients; 32.4%; 1555.7 patient-years of exposure), and biologics (193 patients; 20.5%; 670 patient-years of exposure). Double therapy (corticosteroids and either immunosuppressants and biologics) was used by 236 patients (25.2%), with 173 patient-years of exposure. Triple therapy (corticosteroids, immunosuppressants, and biologics) was used by 70 patients (7.5%) with 18.9 patient-years of exposure. There were 3 cases of PJP, conferring a risk of 0.2 (95% CI, 0.01-1.0) to corticosteroids, 0.1 (95% CI, 0.02-0.5) cases per 100 patient-years of exposure to immunosuppressants, 0.3 (95% CI, 0.04-1.1) cases per 100 patient-years of exposure to biologics, 0.6 (95% CI, 0.01-3.2) cases per 100 patient-years of exposure to double therapy, and 0 (95% CI, 0.0-19.5) cases per 100 patient-years of exposure to triple therapy. Primary prophylaxis for PJP was prescribed to 37 patients, for a total of 24.9 patient-years of exposure. CONCLUSIONS: In a population-based cohort of patients with IBD treated with corticosteroids, immunosuppressants, and biologics, there were only 3 cases of PJP, despite the uncommon use of PJP prophylaxis. Routine administration of PJP prophylaxis in these patients may not be warranted, although it should be considered for high-risk groups, such as patients receiving triple therapy.

Contribution of very low-density lipoprotein triglyceride fatty acids to postabsorptive free fatty acid flux in obese humans.

OBJECTIVE: In the fasting state, plasma free fatty acids (FFA) are thought to derive almost exclusively from adipose tissue lipolysis. However, there are mixed reports as to whether the spillover of fatty acids (FA) from very low-density lipoprotein triglyceride (VLDL-TG) hydrolysis contributes significantly to the plasma FFA pool. Because substantial VLDL-TG fatty acid spillover into the plasma FFA pool would profoundly impact the interpretation of isotope dilution measures of FFA flux, we investigated the contribution of VLDL-TG spillover to plasma FFA appearance. MATERIALS/METHODS: Eighteen obese adults (15 women) participated in these studies. Each volunteer received a primed, continuous infusion of their own ex-vivo labeled ([1-(14)C]triolein) VLDL-TG and a continuous infusion of [U-(13)C]oleate (8 nmol · kg fat free mass(-1) · min(-1)) to measure VLDL-TG and FFA rate of appearance (Ra), respectively. The presence of (14)C-oleate in the plasma FFA-oleate pool was used to calculate the contribution of spillover from VLDL-TG-oleate to the plasma FFA-oleate Ra. RESULTS: The spillover rate of VLDL-TG-oleate into plasma FFA-oleate was 6 ± 2 µmol/min (7% ± 2% of [(14)C]oleate from VLDL-TG) and FFA-oleate flux was 240 ± 61 µmol/min. Thus, only 3% ± 1% of total plasma FFA-oleate appearance could be accounted for by VLDL-TG spillover. CONCLUSION: The contribution of VLDL-TG spillover to the total plasma FFA pool is negligible and will not materially affect the interpretation of FFA flux measures as an index of adipose tissue lipolysis.

Treatment of hyperprolactinemia: a systematic review and meta-analysis.

BACKGROUND: Hyperprolactinemia is a common endocrine disorder that can be associated with significant morbidity. We conducted a systematic review and meta-analyses of outcomes of hyperprolactinemic patients, including microadenomas and macroadenomas, to provide evidence-based recommendations for practitioners. Through this review, we aimed to compare efficacy and adverse effects of medications, surgery and radiotherapy in the treatment of hyperprolactinemia. METHODS: We searched electronic databases, reviewed bibliographies of included articles, and contacted experts in the field. Eligible studies provided longitudinal follow-up of patients with hyperprolactinemia and evaluated outcomes of interest. We collected descriptive, quality and outcome data (tumor growth, visual field defects, infertility, sexual dysfunction, amenorrhea/oligomenorrhea and prolactin levels). RESULTS: After review, 8 randomized and 178 nonrandomized studies (over 3,000 patients) met inclusion criteria. Compared to no treatment, dopamine agonists significantly reduced prolactin level (weighted mean difference, -45; 95% confidence interval, -77 to -11) and the likelihood of persistent hyperprolactinemia (relative risk, 0.90; 95% confidence interval, 0.81 to 0.99). Cabergoline was more effective than bromocriptine in reducing persistent hyperprolactinemia, amenorrhea/oligomenorrhea, and galactorrhea. A large body of noncomparative literature showed dopamine agonists improved other patient-important outcomes. Low-to-moderate quality evidence supports improved outcomes with surgery and radiotherapy compared to no treatment in patients who were resistant to or intolerant of dopamine agonists. CONCLUSION: Our results provide evidence to support the use of dopamine agonists in reducing prolactin levels and persistent hyperprolactinemia, with cabergoline proving more efficacious than bromocriptine. Radiotherapy and surgery are useful in patients with resistance or intolerance to dopamine agonists.