Metabolite Profiling Identifies Candidate Markers Reflecting the Clinical Adaptations Associated with Roux-en-Y Gastric Bypass Surgery

Background

Roux-en-Y gastric bypass (RYGB) surgery is associated with weight loss, improved insulin sensitivity and glucose homeostasis, and a reduction in co-morbidities such as diabetes and coronary heart disease. To generate further insight into the numerous metabolic adaptations associated with RYGB surgery, we profiled serum metabolites before and after gastric bypass surgery and integrated metabolite changes with clinical data.

Methodology and Principal Findings

Serum metabolites were detected by gas and liquid chromatography-coupled mass spectrometry before, and 3 and 6 months after RYGB in morbidly obese female subjects (n = 14; BMI = 46.2±1.7). Subjects showed decreases in weight-related parameters and improvements in insulin sensitivity post surgery. The abundance of 48% (83 of 172) of the measured metabolites changed significantly within the first 3 months post RYGB (p<0.05), including sphingosines, unsaturated fatty acids, and branched chain amino acids. Dividing subjects into obese (n = 9) and obese/diabetic (n = 5) groups identified 8 metabolites that differed consistently at all time points and whose serum levels changed following RYGB: asparagine, lysophosphatidylcholine (C18:2), nervonic (C24:1) acid, p-Cresol sulfate, lactate, lycopene, glucose, and mannose. Changes in the aforementioned metabolites were integrated with clinical data for body mass index (BMI) and estimates for insulin resistance (HOMA-IR). Of these, nervonic acid was significantly and negatively correlated with HOMA-IR (p = 0.001, R = −0.55).

Conclusions

Global metabolite profiling in morbidly obese subjects after RYGB has provided new information regarding the considerable metabolic alterations associated with this surgical procedure. Integrating clinical measurements with metabolomics data is capable of identifying markers that reflect the metabolic adaptations following RYGB.     

Effect of Roux-en-Y Gastric Bypass Surgery on Bile Acid Metabolism in Normal and Obese Diabetic Rats

In addition to classic functions of facilitating hepatobiliary secretion and intestinal absorption of lipophilic nutrients, bile acids (BA) are also endocrine factors and regulate glucose and lipid metabolism. Recent data indicate that antiobesity bariatric procedures e.g. Roux-en-Y gastric bypass surgery (RYGB), which also remit diabetes, increase plasma BAs in humans, leading to the hypothesis that BAs may play a role in diabetes resolution following surgery. To investigate the effect of RYGB on BA physiology and its relationship with glucose homeostasis, we undertook RYGB and SHAM surgery in Zucker diabetic fatty (ZDF) and normoglycemic Sprague Dawley (SD) rats and measured plasma and fecal BA levels, as well as plasma glucose, insulin, Glucagon like peptide 1 (GLP-1) and Peptide YY (PYY), 2 days before and 3, 7, 14 and 28 days after surgery. RYGB decreased body weight and increased plasma GLP-1 in both SD and ZDF rats while decreasing plasma insulin and glucose in ZDF rats starting from the first week. Compared to SHAM groups, both SD-RYGB and ZDF-RYGB groups started to have increases in plasma total BAs in the second week, which might not contribute to early post-surgery metabolic changes. While there was no significant difference in fecal BA excretion between SD-RYGB and SD-SHAM groups, the ZDF-RYGB group had a transient 4.2-fold increase (P<0.001) in 24-hour fecal BA excretion on post-operative day 3 compared to ZDF-SHAM, which paralleled a significant increase in plasma PYY. Ratios of plasma and fecal cholic acid/chenodeoxycholic acid derived BAs were decreased in RYGB groups. In addition, tissue mRNA expression analysis suggested early intestinal BA reabsorption and potentially reduced hepatic cholic acid production in RYGB groups. In summary, we present novel data on RYGB-mediated changes in BA metabolism to further understand the role of BAs in RYGB-induced metabolic effects in humans.     

Plasma MR‐proADM Correlates to BMI and Decreases in Relation to Leptin After Gastric Bypass Surgery

Adrenomedullin (ADM) is a vasoactive peptide found to be related to obesity and its comorbidities: type 2 diabetes, hypertension, atherosclerosis, and coronary heart disease. ADM is increased both in plasma and in adipose tissue of obese individuals when compared to lean subjects and is considered as a member of the adipokine family. We determined plasma midregional proadrenomedullin (MR‐proADM) concentrations in a cohort of 357 subjects with BMI ranging from 17.5 to 42.3 kg/m² and no additional medical history. In parallel, 28 severely obese patients scheduled to undergo laparoscopic Roux‐en‐Y gastric bypass (RYGB) surgery were studied at two time points: before and 1 year after surgery. Outcome measurements were: MR‐proADM, cortisol, leptin, C‐reactive protein (CRP) thyroid‐stimulating hormone (TSH), creatinine and metabolic parameters. BMI correlated significantly to plasma MR‐proADM levels (r = 0.714, P < 0.001), also after adjustment for age and gender (r = 0.767, P < 0.001). In obese subjects, there was a positive relationship between MR‐proADM and leptin (r = 0.511, P = 0.006). Following RYGB, plasma MR‐proADM decreased from 0.76 ± 0.03 to 0.62 ± 0.02 pg/ml (P < 0.0001). RYGB‐induced changes in MR‐proADM correlated significantly to changes in leptin (r = 0.533, P = 0.004) and in CRP (r = 0.429, P = 0.023). We conclude that BMI is an independent predictor of circulating MR‐proADM levels. Weight loss after RYGB is associated with a significant decrease in plasma MR‐proADM, which is related to surgery‐induced changes in both circulating leptin and systemic inflammation.     

Gastric bypass surgery reduces plasma ceramide subspecies and improves insulin sensitivity in severely obese patients

Bariatric surgery is associated with near immediate remission of type 2 diabetes and hyperlipidemia. The mechanisms underlying restoration of normal glucose tolerance postoperatively are poorly understood. Herein, we examined the effect of Roux‐en‐Y gastric bypass surgery (RYGB) on weight loss, insulin sensitivity, plasma ceramides, proinflammatory markers, and cardiovascular risk factors before and at 3 and 6 months after surgery. Thirteen patients (10 female; age 48.5 ± 2.7 years; BMI, 47.4 ± 1.5 kg/m²) were included in the study, all of whom had undergone laparoscopic RYGB surgery. Insulin sensitivity, inflammatory mediators and fasting lipid profiles were measured at baseline, 3 and 6 months postoperatively, using enzymatic analysis. Plasma ceramide subspecies (C14:0, C16:0, C18:0, C18:1, C20:0, C24:0, and C24:1) were quantified using electrospray ionization tandem mass spectrometry after separation with HPLC. At 3 months postsurgery, body weight was reduced by 25%, fasting total cholesterol, triglycerides, low‐density lipoproteins, and free fatty acids were decreased, and insulin sensitivity was increased compared to presurgery values. These changes were all sustained at 6 months. In addition, total plasma ceramide levels decreased significantly postoperatively (9.3 ± 0.5 nmol/ml at baseline vs. 7.6 ± 0.4 at 3 months, and 7.3 ± 0.3 at 6 months, P < 0.05). At 6 months, the improvement in insulin sensitivity correlated with the change in total ceramide levels (r = ?0.68, P = 0.02), and with plasma tumor necrosis factor‐α (TNF‐α) (r = ?0.62, P = 0.04). We conclude that there is a potential role for ceramide lipids as mediators of the proinflammatory state and improved insulin sensitivity after gastric bypass surgery.     

Visceral obesity is a negative predictor of remission of diabetes 1 year after bariatric surgery

Our aim was to identify preoperative anthropometric and clinical parameters that predict the remission of diabetes after Roux‐en‐Y gastric bypass (RYGB). Fifty severely obese Korean patients with type 2 diabetes underwent RYGB. Visceral and abdominal subcutaneous fat area (SFA) was assessed using computed tomography before and 6 and 12 months after RYGB. Remission was defined as a glycated hemoglobin (A_1C) level <6.5% and a fasting glucose concentration <126 mg/dl for 1 year or more without the use of medication. The visceral‐to‐SFA ratio decreased from 0.60 ± 0.30 to 0.53 ± 0.29 (P = 0.001) after 6 months and decreased further to 0.42 ± 0.24 (P < 0.001) after 12 months. Thirty‐four of the 50 patients (68%) had remission of diabetes (remission group). Compared with patients in the nonremission group, patients in the remission group had a shorter duration of diabetes and lower preoperative A_1C level, and were less likely to use insulin preoperatively. Preoperative BMI did not differ in two groups. However, the preoperative visceral‐to‐SFA ratio was greater in the nonremission group compared with the remission group (0.79 ± 0.29 vs. 0.53 ± 0.26, P = 0.003). Finally, the preoperative visceral‐to‐SFA ratio was an independent predictor of the remission of diabetes after RYGB in multiple stepwise logistic regression analysis. In conclusion, our data suggest that visceral adiposity negatively influence the likelihood of the patient experiencing the remission of diabetes after RYGB.     

Acute and long-term effects of Roux-en-Y gastric bypass on glucose metabolism in subjects with Type 2 diabetes and normal glucose tolerance

Our aim was to study the potential mechanisms responsible for the improvement in glucose control in Type 2 diabetes (T2D) within days after Roux-en-Y gastric bypass (RYGB). Thirteen obese subjects with T2D and twelve matched subjects with normal glucose tolerance (NGT) were examined during a liquid meal before (Pre), 1 wk, 3 mo, and 1 yr after RYGB. Glucose, insulin, C-peptide, glucagon-like peptide-1 (GLP-1), glucose-dependent-insulinotropic polypeptide (GIP), and glucagon concentrations were measured. Insulin resistance (HOMA-IR), β-cell glucose sensitivity (β-GS), and disposition index (D(β-GS): β-GS × 1/HOMA-IR) were calculated. Within the first week after RYGB, fasting glucose [T2D Pre: 8.8 ± 2.3, 1 wk: 7.0 ± 1.2 (P < 0.001)], and insulin concentrations decreased significantly in both groups. At 129 min, glucose concentrations decreased in T2D [Pre: 11.4 ± 3, 1 wk: 8.2 ± 2 (P = 0.003)] but not in NGT. HOMA-IR decreased by 50% in both groups. β-GS increased in T2D [Pre: 1.03 ± 0.49, 1 wk: 1.70 ± 1.2, (P = 0.012)] but did not change in NGT. The increase in DI(β-GS) was 3-fold in T2D and 1.5-fold in NGT. After RYGB, glucagon secretion was increased in response to the meal. GIP secretion was unchanged, while GLP-1 secretion increased more than 10-fold in both groups. The changes induced by RYGB were sustained or further enhanced 3 mo and 1 yr after surgery. Improvement in glycemic control in T2D after RYGB occurs within days after surgery and is associated with increased insulin sensitivity and improved β-cell function, the latter of which may be explained by dramatic increases in GLP-1 secretion.     

Gastric bypass surgery reveals independency of obesity and diabetes melitus type 2

Background

Roux-en-Y gastric bypass surgery is widely applied to ameliorate morbid obesity, including diabetes in people with type 2 diabetes. The latter vanish a few days after surgery for many, but not in all patients before any weight reduction has occurred. The explanation for this change in metabolic status is poorly understood, but the observation may suggest that the fate obesity and diabetes is only partly linked after surgery.

Methods

The trajectories of weight reduction measured as reduced body mass index (BMI) in 741obese subjects with and without diabetes were evaluated. Evaluation was performed on three groups: 1) subjects that were non-diabetic before and after surgery; 2) subjects that were diabetics before surgery but non-diabetics after surgery; and 3) subjects that were diabetics before surgery and remained diabetics after surgery. The diabetic state was established at HbA1c above 48 mmol/mol.

Results

The trajectories differ significantly between groups and any sub-populations of groups, the latter identified by the distance between individual trajectories using a k-means procedure. The results suggest that different domains in the enormous genetic network governing basic metabolism are perturbed in obesity and diabetes, and in fact some of the patients are affected by two distinct diseases: obesity and diabetes mellitus type 2.

Conclusion

Although RYGB “normalized” many glycaemic parameters in some of the diabetic subjects apparently converting to a non-diabetics state, other diabetic subjects stay diabetic in the context of the new gut anatomy after surgery. Thus, the obesity part of the glycaemic derangement may have been ameliorated, but some defects of the diabetic state had not.

     

Impaired fatty acid metabolism in type 2 diabetic skeletal muscle cells is reversed by PPARgamma agonists

The impact of type 2 diabetes on the ability of muscle to accumulate and dispose of fatty acids and triglycerides was evaluated in cultured muscle cells from nondiabetic (ND) and type 2 diabetic (T2D) subjects. In the presence of 5 microM palmitate, T2D muscle cells accumulated less lipid than ND cells (11.5 +/- 1.2 vs. 15.1 +/- 1.4 nmol/mg protein, P < 0.05). Chronic treatment (4 days) with the peroxisome proliferator-activated receptor-gamma (PPARgamma) agonist troglitazone increased palmitate accumulation, normalizing uptake in T2D cells. There were no significant differences between groups with regard to the relative incorporation of palmitate into neutral lipid species. This distribution was also unaffected by troglitazone treatment. beta-Oxidation of both long-chain (palmitate) and medium-chain (octanoate) fatty acids in T2D muscle cells was reduced by approximately 40% compared with ND cells. Palmitate oxidation occurred primarily in mitochondrial ( approximately 40-50% of total) and peroxisomal (20-30%) compartments. The diabetes-related defect in palmitate oxidation was localized to the mitochondrial component. Both palmitate and octanoate oxidation were stimulated by a series of thiazolidinediones. Oxidation in T2D muscle cells was normalized after treatment. Troglitazone increased the mitochondrial component of palmitate oxidation. Skeletal muscle cells from T2D subjects express defects in free fatty acid metabolism that are retained in vitro, most importantly defects in beta-oxidation. These defects can be corrected by treatment with PPARgamma agonists. Augmentation of fatty acid disposal in skeletal muscle, potentially reducing intramyocellular triglyceride content, may represent one mechanism for the lipid-lowering and insulin-sensitizing effects of thiazolidinediones.     

Interactions of insulin, corticosterone and prolactin in promoting milk-fat synthesis by mammary explants from pregnant rabbits

1. The rate of fatty acid synthesis by mammary explants from rabbits pregnant for 16 days or from rabbits pseudopregnant for 11 days was stimulated up to 15-fold by culturing for 2-4 days with prolactin. This treatment initiated the predominant synthesis of C(8:0) and C(10:0) fatty acids, which are characteristic of rabbit milk. 2. Inclusion of insulin in the culture medium increased the rate of synthesis of these medium-chain fatty acids. By contrast the inclusion of corticosterone led to the predominant synthesis of long-chain fatty acids. When explants were cultured for 2-4 days with insulin, corticosterone and prolactin, the rate of fatty acid synthesis increased up to 42-fold, but both medium- and long-chain fatty acids were synthesized. 3. These results show that the stimulus to mammary-gland lipogenesis and the initiation of synthesis of medium-chain fatty acids observed between days 16 and 23 of pregnancy in the rabbit can be simulated in vitro by prolactin alone. 4. When mammary explants from rabbits pregnant for 23 days were cultured for 2 days with insulin, corticosterone and prolactin, the rate of fatty acid synthesis increased fivefold, but there was a preferential synthesis of long-chain fatty acids. Culture with prolactin alone had little effect on the rate or pattern of fatty acids synthesized. 5. The results are compared with findings in vivo on the control of lipogenesis in the rabbit mammary gland, and are contrasted with the known effects of hormones in vitro on the mammary gland of the mid-pregnant mouse.     

METABOLISM OF BRAIN SPHINGOMYELINS: HALF-LIVES OF SPHINGOSINE, FATTY ACIDS AND PHOSPHATE FROM TWO TYPES OF RAT BRAIN SPHINGOMYELIN

Abstract— The metabolism of rat brain sphingomyelins containing short-chain (C₁₆-C₁₈) and long-chain (C₂₀- C₂₄) fatty acids has been studied by determination of the content of radioactivity in the sphingo-sinc. fatty acids and phosphate of the sphingomyelins over a period of 60 days following the intracisternal injection of [¹⁴C]acetate and [³²P]phosphate. From the rate of decrease of the specific radioactivities of the different constituents of short-chain fatty acid sphingomyelins, we have calculated a half-life of 65 days for sphingosine. 41 days for fatty acids and 62 days for phosphate. For the long-chain fatty acid sphingomyelins the half-life of sphingosine was approximately 465 days. The fatty acids and phosphate from these sphingomyelins had fast and slow turnover pools. The half-life for the fast pool was 7 days for the two constituents and the estimated half-lives for the slow pool were 220 days for fatty acids and 480 days for phosphate. These results suggest that one can distinguish at least three metabolic pools of brain sphingomyelins: (a) sphingomyelins with long-chain fatty acids situated in myelin whose half-lives are 465 days for sphingosine, 220 days for fatty acids and 480 days for phosphate; (b) sphingomyelins with long-chain fatty acids located mainly in non-myelin structures having half-lives of 465 days for sphingosine. 7 days for fatty acids and 7 days for phosphate; (c) sphingomyeiins with short-chain fatty acids with half-lives of 65 days for sphingosine. 41 days for fatty acids and 62 days for phosphate. The differences between the half-lives of the three metabolic pools of sphingomyelin, together with the subcellular localizations of the two molecular species of these compounds, suggest that the metabolism of the different molecular species of sphingomyelin are independent and that in various subcellular fractions the long-chain fatty acid and short-chain fatty acid sphingomyelins have different turnover rates.     

Moderate effect of duodenal-jejunal bypass surgery on glucose homeostasis in patients with type 2 diabetes

Gastric bypass surgery causes resolution of type 2 diabetes (T2DM), which has led to the hypothesis that upper gastrointestinal (UGI) tract diversion, itself, improves glycemic control. The purpose of this study was to determine whether UGI tract bypass without gastric exclusion has therapeutic effects in patients with T2DM. We performed a prospective trial to assess glucose and β-cell response to an oral glucose load before and at 6, 9, and 12 months after duodenal-jejunal bypass (DJB) surgery. Thirty-five overweight or obese adults (BMI: 27.0 ± 4.0 kg/m(2)) with T2DM and 35 sex-, age-, race-, and BMI-matched subjects with normal glucose tolerance (NGT) were studied. Subjects lost weight after surgery, which was greatest at 3 months (6.9 ± 4.9%) with subsequent regain to 4.2 ± 5.3% weight loss at 12 months after surgery. Glycated hemoglobin (HbA(1c)) decreased from 9.3 ± 1.6% before to 7.7 ± 2.0% at 12 months after surgery (P < 0.001), in conjunction with a 20% decrease in the use of diabetes medications (P < 0.05); 7 (20%) subjects achieved remission of diabetes (no medications and HbA(1c) <6.5%). The area under the curve after glucose ingestion was ~20% lower for glucose but doubled for insulin and C-peptide at 12 months, compared with pre-surgery values (all P < 0.01). However, the β-cell response was still 70% lower than subjects with NGT (P < 0.001). DJB surgery improves glycemic control and increases, but does not normalize the β-cell response to glucose ingestion. These findings suggest that altering the intestinal site of delivery of ingested nutrients has moderate therapeutic effects by improving β-cell function and glycemic control.     

Modulation of cholesterol concentration in Caco-2 cells by incubation with different n-6 fatty acids

Incorporation of exogenous cholesterol was compared in human adenocarcinoma colon cells (Caco-2) after incubation with 100 microM of either linoleic acid (LA, 18:2n-6), gamma-linolenic acid (GLA, 18:3n-6), arachidonic acid (AA, 20:4n-6) or adrenic acid (or n-6 docosatetraenoic acid, DTA, 22:4n-6). In both cells 7 days after seeding and 14 days after confluency, incubation with LA significantly raised the proportion of 18:2n-6 but not its long-chain metabolites in cellular phospholipid. Incubation with GLA increased the levels of 18:3n-6, 20:3n-6, and 20:4n-6. Incubation with AA increased the levels of 20:4n-6 and 22:4n-6, and incubation with DTA increased the levels of 22:4n-6 as well as its retro-conversion metabolite, 20:4n-6. A subsequent addition of cholesterol (180 microM) to the medium significantly raised the cellular cholesterol level but less so in the cells 7 days after seeding incubated with GLA. The increase in cellular cholesterol level was generally greater in the cells of 7 days after seeding, particularly those incubated with long-chain highly unsaturated n-6 fatty acids, than in those of 14 days after confluency. These findings suggest that the cell growth and the extent of unsaturation in cell membrane phospholipid fatty acids modulate the incorporation of the exogenous cholesterol into the Caco-2 cells.     

Rapid effects of the intravenous injection of a medium-chain triglyceride: fish oil emulsion on the triglyceride fatty acid pattern of soleus muscle from omega3 fatty acid-depleted rats.

Second generation rats depleted in long-chain polyunsaturated omega3 fatty acids display several features of the metabolic syndrome, including visceral obesity, liver steatosis, insulin resistance, hypertension, and cardiac hypertrophy. In the framework of an extensive study on such metabolic, hormonal and functional perturbations, the phospholipid fatty acid pattern and ex vivo metabolism of D-glucose were recently investigated in the soleus muscle of these omega3-depleted rats. The present study deals with the triglyceride fatty acid content and pattern of the soleus muscle in control animals and omega3-depleted rats. Some of the latter rats were injected intravenously 60-120 minutes before sacrifice with either an omega3 fatty acid-rich medium-chain triglyceride/fish oil emulsion (omega3-FO rats) or a control medium-chain triglyceride/olive oil emulsion (omega3-OO rats). The total fatty acid content of triglycerides was comparable in control and omega3-depleted rats and, in both cases, inversely related to their C20:4omega6 relative content. At variance with the situation found in control rats, no long-chain polyunsaturated omega3 fatty acid (C18:3omega3, C20:5omega3, C22:5omega3, C22:6omega3) was detected in the omega3-depleted rats. Unexpectedly, the triglyceride content in most long-chain polyunsaturated omega6 fatty acids (C18:2omega6, C20:3omega6, C20:4omega6 and C22:4omega6) had also decreased in the latter rats. Moreover, the activity of Delta9-desaturase was apparently increased in the omega3-depleted rats, as judged from the C16:1omega7/C16:0 and C18:1omega9/C18:0 ratios. The omega3-FO rats differed from omega3-OO rats by a lower contribution of C18:2omega6 metabolites (C18:3omega6, C20:3omega6, C20:4omega6 and C22:4omega6). These findings indicate that the prior injection of the medium-chain triglyceride/fish oil emulsion, known to increase the muscle phospholipid content in long-chain polyunsaturated omega3 fatty acids, may nevertheless accentuate the depletion in long-chain polyunsaturated omega6 fatty acids otherwise found in the triglycerides of omega3-depleted rats. Such a dual effect is reminiscent of that observed, under the same experimental conditions, for selected variables in D-glucose metabolism in the soleus muscle.     

Particular characteristics of the metabolic syndrome in patients with morbid obesity

BackgroundCriteria for the diagnosis of the metabolic syndrome are currently being reconsidered, as their usefulness is not the same for all phenotypes in relation to the risk of cardiovascular disease.AimWe analyzed the changes in metabolic parameters after a fat overload in different groups of patients.Materials and methodsThe study included 20 healthy persons, 30 metabolic syndrome patients without morbid obesity, 80 metabolic syndrome patients with morbid obesity and 16 patients with morbid obesity without the metabolic syndrome. All the participants received a fat overload of 60 g. Measurements were made before the overload and 3 h afterwards of triglycerides, free fatty acids, insulin and uric acid.ResultsMetabolic syndrome patients with morbid obesity had a lower waist-to-hip ratio, and lower plasma free fatty acid and triglycerides levels at baseline and after the overload than patients without morbid obesity. Plasma uric acid levels rose after the fat overload in the metabolic syndrome patients who had morbid obesity but not in the patients without morbid obesity. A positive relation was found between plasma triglycerides and free fatty acid levels in all the patients but not in the controls after the fat overload. A positive relation was also found between uric acid and insulin levels in the metabolic syndrome patients with morbid obesity.ConclusionsMetabolic syndrome patients with and without morbid obesity presented different metabolic characteristics. This suggests that there are 2 different clinical phenotypes, both grouped under the metabolic syndrome umbrella.     

True fractional calcium absorption is decreased after Roux-en-Y gastric bypass surgery

Objective: Roux‐en‐Y gastric bypass (RYGB) is considered to be the gold standard alternative treatment for severe obesity. Weight loss after RYGB results primarily from decreased food intake. Inadequate calcium (Ca) intake and metabolic bone disease can occur after gastric bypass. To our knowledge, whether malabsorption of Ca contributes to an altered Ca metabolism in the RYGB patient has not been addressed previously. Research Methods and Procedures: We recruited 25 extremely obese women in order to study true fractional Ca absorption (TFCA) before and 6 months after RYGB surgery, using a dual stable isotope method (⁴²Ca and ⁴³Ca) and test load of Ca (200 mg). Hormones regulating Ca absorption and markers of bone turnover were also measured. Results: In 21 women (BMI 52.7 ± 8.3 kg/m², age 43.9 ± 10.4 years) who successfully completed the study, TFCA decreased from 0.36 ± 0.08 to 0.24 ± 0.09 (p < 0.001) after RYGB. Bone turnover markers increased significantly (p < 0.01). TFCA correlated with estradiol levels (r = 0.512, p < 0.02) and tended to correlate with 1,25 (OH)₂D (r = 0.427, p < 0.06) at final measurement. Stepwise linear regression indicated that estradiol explained 62% of the variance for TFCA at 6 months post‐surgery (p < 0.01). Discussion: TFCA decreases (0.12 ± 0.08) after RYGB surgery but remains within normal range. Although only some patients were estimated to have low Ca absorption after surgery, all of the patients showed a dramatic increase in markers of bone resorption. The alteration in Ca metabolism after RYGB‐induced weight loss appears to be regulated primarily by estradiol levels and might ultimately affect bone mass.     

Improved energy homeostasis of the heart in the metabolic state of exercise

We postulate that metabolic conditions that develop systemically during exercise (high blood lactate and high nonesterified fatty acids) are favorable for energy homeostasis of the heart during contractile stimulation. We used working rat hearts perfused at physiological workload and levels of the major energy substrates and compared the metabolic and contractile responses to an acute low-to-high work transition under resting versus exercising systemic metabolic conditions (low vs. high lactate and nonesterified fatty acids in the perfusate). Glycogen preservation, resulting from better maintenance of high-energy phosphates, was a consequence of improved energy homeostasis with high fat and lactate. We explained the result by tighter coupling between workload and total beta-oxidation. Total fatty acid oxidation with high fat and lactate reflected increased availability of exogenous and endogenous fats for respiration, as evidenced by increased long-chain fatty acyl-CoA esters (LCFA-CoAs) and by an increased contribution of triglycerides to total beta-oxidation. Triglyceride turnover (synthesis and degradation) also appeared to increase. Elevated LCFA-CoAs caused high total beta-oxidation despite increased malonyl-CoA. The resulting bottleneck at mitochondrial uptake of LCFA-CoAs stimulated triglyceride synthesis. Our results suggest the following. First, both malonyl-CoA and LCFA-CoAs determine total fatty acid oxidation in heart. Second, concomitant stimulation of peripheral glycolysis and lipolysis should improve cardiac energy homeostasis during exercise. We speculate that high lactate contributes to the salutary effect by bypassing the glycolytic block imposed by fatty acids, acting as an anaplerotic substrate necessary for high tricarbocylic acid cycle flux from fatty acid-derived acetyl-CoA.     

Components of Total Energy Expenditure in Healthy Young Women Are Not Affected after 14 Days of Feeding with Medium-Versus Long-Chain Triglycerides

PAPAMANDJARIS, ANDREA A., MATTHEW D. WHITE, AND PETER J. H. JONES. Components of total energy expenditure in healthy young women are not affected after 14 days of feeding with medium-versus long-chain triglycerides. Obes Res. Objective: To examine the effect of consumption of medium-chain triglycerides (MCT) vs. long-chain triglycerides (LCT) on total energy expenditure (TEE) and its components in young women during the second week of a 2-week feeding period. Research Methods and Procedures: Twelve healthy lean women (age: 22. 7±0. 7 years, body mass index [BMI]: 21. 5±0. 8 kg/m²) were fed weight maintenance diets containing 15% of energy as protein, 45% as carbohydrate, and 40% as fat, 80% of which was treatment fat, for 2 weeks in a randomized cross-over design separated by a 2-week washout period. Dietary fat was composed of triglycerides containing either 26% medium-chain fatty acids (MCFA) and 74% long-chain fatty acids (LCFA), or 2% MCFA and 98% LCFA. Free-living TEE was measured from day 7 to 14 on each dietary treatment using doubly labeled water (DLW). Basal metabolic rate (BMR) and thermic effect of food (TEF) were measured on days 7 and 14 using respiratory gas exchange analysis (RGE) for 30 minutes and 330 minutes, respectively. Activity-induced energy expenditure (AIEE) was derived as the difference between TEE and the sum of BMR and TEF. Results: The average TEE while consuming the MCT diet (2246±98 kcal/day) did not differ from that of the LCT diet (2186±138 kcal/day. BMR was significantly higher on the MCT diet on day 7 (1219±38 kcal/day vs. 1179±42 kcall day), but not on day 14; there was no effect of diet on TEF. There were no differences in BMR, TEF, or AIEE between diets when expressed as percentages of TEE. On average, BMR, TEF, and AIEE represented 54. 6%, 8. 2%, and 37. 2%, respectively, of TEE. Discussion: Results suggest that between day 7 and day 14 feeding of MCT vs. LCT at these levels, TEE is not affected and that increases seen in energy expenditure following MCT feeding may be of short duration. Thus, compensatory mechanisms may exist which blunt the effect of MCT on energy components over the longer term.     

Lipoprotein lipase in plasma after an oral fat load: relation to free fatty acids.

Lipoprotein lipase (LPL) releases fatty acids from triglyceride-rich lipoproteins for use in cellular metabolic reactions. How this hydrolysis, which occurs at the vascular endothelium, is regulated is poorly understood. A fatty acid feedback system has been proposed by which accumulation of fatty acids impedes LPL-catalyzed hydrolysis and dissociates the enzyme from its endothelial binding sites. We examined this hypothesis in humans who were subjected to an oral fat tolerance test of a mixed-meal type. Plasma triglycerides, free fatty acids, and LPL activity were measured before and repeatedly during a 12-h period after intake of the fat load. Since soybean oil with a high content of linoleic fatty acid was the source of triglycerides, a distinction could be made between endogenous free fatty acids (FFA) and FFA derived directly from lipolysis of postprandial triglyceride-rich lipoproteins. Mean LPL activity was almost doubled (P less than 0.01) 6 h after intake of the oral fat load. The rise in LPL activity was accompanied by an increase of plasma triglycerides and linoleic free fatty acids (18:2 FFA), but not of total plasma FFA, which instead displayed a heterogeneous pattern with essentially unchanged mean levels. The postprandial response of LPL activity largely paralleled the postprandial responses of 18:2 FFA and triglycerides. The highest degree of parallelism was seen between postprandial 18:2 FFA and LPL activity levels. Furthermore, the integrated response (area under the curve, AUC) for plasma measurements of LPL correlated with the AUC for 18:2 FFA (r = 0.40, P less than 0.05), but not with the AUC for plasma triglycerides (r = 0.21, ns). The high degree of parallelism and significant correlation between postprandial plasma LPL activity and 18:2 FFA support the hypothesis of fatty acid control of endothelial LPL during physiological conditions in humans.