The American Journal of Medicine
Volume 121, Issue 11 , Pages 966-973, November 2008

Dramatic Reversal of Derangements in Muscle Metabolism and Left Ventricular Function After Bariatric Surgery

  • Joshua G. Leichman, MD

      Affiliations

    • Department of Internal Medicine, The University of Texas Health Science Center at Houston
    • ,
  • Erik B. Wilson, MD

      Affiliations

    • Department of Surgery, The University of Texas Health Science Center at Houston
    • ,
  • Terry Scarborough, MD

      Affiliations

    • Department of Surgery, The University of Texas Health Science Center at Houston
    • ,
  • David Aguilar, MD

      Affiliations

    • Department of Internal Medicine, The University of Texas Health Science Center at Houston
    • ,
  • Charles C. Miller III, PhD

      Affiliations

    • Department of Cardiovascular and Thoracic Surgery, The University of Texas Health Science Center at Houston
    • ,
  • Sherman Yu, MD

      Affiliations

    • Department of Surgery, The University of Texas Health Science Center at Houston
    • ,
  • Mohamed F. Algahim, BSc

      Affiliations

    • Department of Internal Medicine, The University of Texas Health Science Center at Houston
    • ,
  • Manuel Reyes, MD

      Affiliations

    • Department of Internal Medicine, The University of Texas Health Science Center at Houston
    • ,
  • Frank G. Moody, MD

      Affiliations

    • Department of Surgery, The University of Texas Health Science Center at Houston
    • ,
  • Heinrich Taegtmeyer, MD, DPhil

      Affiliations

    • Department of Internal Medicine, The University of Texas Health Science Center at Houston
    • Corresponding Author InformationRequests for reprints should be addressed to Heinrich Taegtmeyer, MD, DPhil, University of Texas Houston Medical School, Department of Medicine/Cardiology, 6431 Fannin, MSB 1.246, Houston, TX 77030

Article Outline

Abstract 

Objective

The study objective was to define muscle metabolic and cardiovascular changes after surgical intervention in clinically severe obese patients.

Methods

Obesity is a state of metabolic dysregulation that can lead to maladaptive changes in heart and skeletal muscle, including insulin resistance and heart failure. In a prospective longitudinal study, 43 consecutive patients underwent metabolic profiling, skeletal muscle biopsies, and resting echocardiograms at baseline and 3 and 9 months after bariatric surgery.

Results

Body mass index decreased (mean changes, 95% confidence interval [CI]): 7.7 kg/m2 (95% CI, 6.70-8.89) at 3 months and 5.6 kg/m2 (95% CI, 4.45-6.80; P<.0001) at 9 months after surgery, with restoration of insulin sensitivity and decreases in plasma leptin at the same time points. Concurrent with these changes were dramatic decreases in skeletal muscle transcript levels of stearoyl coenzyme-A desaturase and pyruvate dehydrogenase kinase-4 at 3 and 9 months (P<.0001, for both) and a significant decrease in peroxisome proliferation activated receptor-α–regulated genes at 9 months. Left ventricular relaxation impairment, assessed by tissue Doppler imaging, normalized 9 months after surgery.

Conclusion

Weight loss results in the reversal of systemic and muscle metabolic derangements and is accompanied by a normalization of left ventricular diastolic function.

Keywords: Bariatric surgery, Echocardiography, Leptin, Metabolism, Obesity, Pyruvate dehydrogenase kinase-4, Stearoyl Co-A desaturase

 

Obesity is a state of metabolic dysregulation with an increased risk for premature death and disability.1 The maladaptive response of obesity has been attributed to metabolic changes caused by increased energy substrate supply, decreased energy substrate use, or both. The body's initial response is to store the energy excess in adipose tissue, to increase cardiac mass in response to the hemodynamic load associated with obesity, and to up-regulate gene expression to account for changing metabolic demands. It has been suggested that when the storage capacity of the adipocyte is exhausted there is “spillover” to other organs of the body.2 Lipid accumulation in nonadipose tissue is a hallmark of dysregulated local and systemic metabolism,3, 4 insulin resistance,5 and possibly the development of heart failure.6, 7

Clinical Significance

 


•Obesity is associated with metabolic dysregulation.

•Maladaptive changes in heart and skeletal muscle include insulin resistance and cardiac contractile dysfunction.

•Forty-three severely obese patients (body mass index 51 kg/m2) were studied by metabolic profiling, skeletal muscle biopsies, and resting echocardiograms before and 3 and 9 months after weight loss surgery.

•Weight loss resulted in an early and sustained reversal of systemic and muscle metabolic derangements and a normalization of left ventricular diastolic function.

Obesity has reached epidemic proportions, and obesity-related illness consumes billions of dollars in health care.8 In addition to premature heart disease, obesity is linked to cancer, sleep apnea, and birth defects. Treatment of obesity should therefore be an important determinant for a normal life expectancy and quality of life. Weight reduction can ameliorate many of the comorbid conditions associated with obesity.9 Indeed, bariatric surgery for severe obesity is associated with survival benefits.10, 11, 12 The metabolic changes that accompany significant weight loss are paramount for these provide outcomes. We proposed that there is a potential for reversal of the maladaptive processes of obesity with sustained weight loss after bariatric surgery.

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Materials and Methods 

Subject Selection 

We offered participation to patients of any race/ethnicity from the University of Texas Houston Bariatric Surgery Center who met the inclusion criteria for bariatric surgery outlined previously.13 Exclusion criteria were coronary artery disease, ischemic cardiomyopathy, severe peripheral vascular disease, a current history of smoking, pregnancy, or an age of less than 18 years. The study was approved by the Committee for the Protection Human Subjects at The University of Texas Health Science Center–Houston. All patients signed an informed consent form before enrollment in the study.

Study Protocol 

We prospectively enrolled 43 consecutive patients. The study protocol has been published.13 Briefly, patients underwent a physical examination, anthropometric measurements, a 12-lead electrocardiogram, and a resting echocardiogram. At the time of surgery, a skeletal muscle biopsy was performed. All studies were repeated at 3 and 9 months postoperatively.

Surgery 

Patients were offered 2 types of bariatric surgery. The patients chose which surgery they preferred to have, because this is the current standard practice in the United States.14 The majority (n=30) chose laparoscopic small pouch gastric bypass (SPGB) with a Roux-en-Y procedure; the others (n=13) chose a laparoscopic adjustable gastric banding (LAGB) procedure. Both procedures are well described in the literature.15, 16

Patient Enrollment and Follow-up 

Of the 43 patients enrolled, 6 were lost to follow-up at 9 months. Reasons for the loss to follow-up were either the inability to contact the patients or the patients' stated unwillingness to continue with the study. Of the 6 patients who were lost to follow-up, 5 underwent SPGB and 1 underwent LAGB. Of the remaining 37 patients (86%), 6 had inadequate baseline echocardiograms and 4 had limited studies because of technical difficulties resulting from body habitus. All patients had skeletal muscle biopsies at baseline, but only 25 patients completed the follow-up at 3 and 9 months. Reasons for the lower completion rate of the skeletal muscle biopsies were fear of pain, a stated discomfort during the procedure, or (in 2 instances) our inability to obtain an adequate sample for analysis.

Biopsies 

At the time of surgery, and at 3 and 9 months after surgery, a percutaneous biopsy of the vastus lateralis was obtained using a 6 G×4.75-inch biopsy needle (Popper and Sons, New Hyde Park, NY). Tissue samples were immediately placed in liquid nitrogen and stored at −80° C until analyzed.

Histology 

Oil-red-O staining was performed on skeletal muscle sections by the Department of Pathology at The University of Texas Medical School at Houston using standard procedures. Photomicrographs of (10×) stained sections were taken on a Zeiss Axiophoto microscope (Carl Zeiss Surgical Inc, Dublin, Calif) using a Leitz Microlumina digital camera. Oil-red-O staining was quantified using Image Pro Plus software with color cube-based selection criteria to ensure that only stained regions were counted as described previously.6 We examined 4 sections for each patient at each of the time points. The results are expressed as a percentage of the stained area (arbitrary units).

Quantitative Reverse Transcriptase Polymerase Chain Reaction 

RNA was extracted from skeletal muscle biopsies by standard methods, and RNA concentrations were measured spectrophotometrically.17 Transcript levels were measured by reverse transcription followed by real-time quantitative polymerase chain reaction as described before.17 We focused on enzymes of fatty acid metabolism, especially those regulated by the peroxisome proliferation activated receptor (PPAR)-α, including carnityl palmitoyl transferase 1, medium chain acetyl CoA dehydrogenase, uncoupling protein 3, and pyruvate dehydrogenase kinase-4 (PDK-4). We also analyzed gene transcript levels for human stearoyl CoA desaturase (SCD). The nucleotide sequences for probes and the forward and reverse primers for the quantitative polymerase chain reaction assays have been published,18 with the exceptions of SCD (forward primer, 5′-TGGTGATGTTCCAGAGGAGGTACT-3′; reverse primer, 5′-AACGAACACACTGTTTTGAAAAGTTT-3′; and probe, 5′-FAM-CCTGGCTTGCTGATGATGTGCTTCA-TAMRA3). Transcript levels were normalized to 2 internal controls and referenced to total RNA content.

Statistical Analyses 

Statistical analyses were performed with the Statistical Package for the Social Sciences 14.0 (SPSS Inc, Chicago, Ill). Significance levels were set at α=0.05. We evaluated all of the study variables for conformation to normality using Q-Q plots, skewness, and kurtosis statistics. Significantly non-normal variables were transformed before analysis. Independent sample t tests were performed to evaluate differences in outcomes between the patients who underwent LAGB and the patients who underwent laparoscopic small pound gastric bypass. Repeated-measures analyses of variance were performed to evaluate the effects at 3 and 9 months postoperatively. Effect of surgery was assessed as a variable between subjects with the repeated-measures analysis of variance. Data are expressed as mean values plus or minus the standard error of the mean and as the change in mean values from baseline to 3 months postoperatively, and from 3 months to 9 months postoperatively with 95% confidence intervals (CI). Pearson correlation coefficients were prepared to evaluate the univariate relationships.

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Results 

Preoperative Findings 

Table 1 lists the baseline characteristics of all patients, the patients undergoing SPGB, and the patients undergoing LAGB. There were no significant differences in the baseline characteristics between the 2 surgical groups for any of the variables measured. Patients had more fat mass than lean body mass at baseline, as measured by bioelectrical impedance analysis (Table 1). Mean blood pressure and heart rates were in the normal range. Almost all of the patients met criteria for insulin resistance, but only 35% of the patients had frank diabetes mellitus. Fasting plasma free fatty acid (FFA) levels were elevated, and leptin levels were approximately 3 times higher than the reference range.

Table 1. Baseline Characteristics
All (n=43)SPGB⁎ (n=30)LAGB⁎ (n=13)
Age(y)45(1.6)43(2.0)49(2.5)
Female(%)86%83%92%
Ethnic Data
White72%67%84%
African-American21%26%8%
Hispanic7%7%8%
Clinical Data
Weight(kg)142(6.2)140(7.9)147(10.5)
BMI(kg/m2)51(1.7)50(2.2)53(2.9)
Waist circumference (cm)136(3.1)134(3.8)139(5.6)
Fat mass(kg)†40(2.6)40(3.5)39(3.0)
Lean mass(kg)†35(2.6)36(3.5)30(2.6)
Hemodynamic Data
SBP(mm Hg)133(2.9)134(3.7)130(4.0)
DBP(mm Hg)74(2.0)74(2.5)74(3.4)
HR(bpm)78(1.7)79(2.3)78(2.2)
Metabolic Data
Glucose(mg/dL)114(9.6)121(13.4)98(6.0)
Insulin(μU/mL)22(2.5)21(2.6)24(5.7)
FFA(mmol/L)0.84(0.03)0.83(0.04)0.84(0.06)
Triglycerides(mg/L)142(20)149(28)126(14)
Leptin(ng/mL)58(4.3)58(5.3)58(7.3)
Comorbidities
Insulin resistance95%93%100%
Diabetes35%36%30%
Hypertension53%56%46%
Dyslipidemia26%30%15%
Medication Use
Antihypertensive drugs48%53%38%
Oral hypoglycemic drugs23%23%23%
Lipid-lowering drugs23%26%15%

SPGB=small pouch gastric bypass; LAGB=laparoscopic adjustable gastric banding; BMI=body mass index; SBP=systolic blood pressure; DBP=diastolic blood pressure; HR=heart rate; FFA=free fatty acid.

All values are the mean±standard error(given in parentheses).

⁎Independent samples t tests for SPGB versus LAGB showed no significant differences for all parameters.

†Body mass as measured by bioelectrical impedance analysis(see “Materials and Methods”).

Postoperative Changes 

Weight and Hemodynamic Parameters 

For practical purposes we chose to analyze patients who underwent laparoscopic SPGB and those who selected LAGB as 1 group. Table 2 shows the parameters at 3 and 9 months after surgery. Weight, body mass index, waist circumference, and fat mass decreased at a faster rate during the first 3 months than during the subsequent 6 months. Fat mass changed to a greater extent than lean mass (Table 2). Lean mass decreased to a greater extent during the first 3 months compared with the subsequent 6 months (0.73 kg/month in the first 3 months vs 0.16 kg/month during the last 6 months).

Table 2. Clinical, Hemodynamic, and Metabolic Changes After Surgery
Months 0 to 3 Mean Difference⁎Significance (P value)†Months 3 to 9 Mean Difference⁎Significance (P value)†
Clinical Data
Weight (kg)21.5(18.1-25.0)<.000116.4(12.8-20.1)<.0001
BMI(kg/m2)7.7(6.7-8.9)<.00015.6(4.4-6.8)<.0001
Waist circumference(cm)9.7(−1.5-21.0)NS16.0(5.6-26.3)<.005
Fat mass(kg)8.3(6.2-10.5)<.00016.1(4.8-7.5)<.0001
Lean mass(kg)2.2(1.4-3.1)<.00011.0(0.7-1.5)<.0001
Hemodynamics Data
SBP(mm Hg)‡1.3(−6.2-9.0)NS4.4(−1.3-10.2)NS
DBP(mm Hg)3.9(−1.1-9.0)NS1.7(−3.5-6.8)NS
HR(beats/min)10.0(5.5-14.5)<.00012.4(−3.1-8.0)NS
Metabolic Data
Glucose(mg/dL)19.1(5.0-33.2)<.012.0(−7.2-11.2)NS
Insulin(μU/mL)11.2(5.6-16.8)<.0001−0.5(−3.2-3.1)NS
HOMA-S(%)−31.2(−46.6-15.8)<.0001−45.2(−77.7-12.7)<.0001
FFA(mmol/L)−0.03(−0.15-0.09)NS0.2(0.1-0.3)<.001
Triglycerides(mg/dL)43.9(5.9-93.7)NS18.7(7.2-30.3)<.005
Leptin(mg/mL)27.2(20.8-33.5)<.00017.7(2.7-12.7)<.005

BMI=body mass index; CI=confidence interval; BMI=body mass index; SBP=systolic blood pressure; DBP=diastolic blood pressure; HOMA-S= homeostatic model of assessment for insulin sensitivity; HR=heart rate; FFA=free fatty acid; NS=not significant.

All values are the mean differences (95% confidence interval in parentheses) of 36 patients.

⁎Mean difference is a decrease in the outcome value unless indicated by a negative value.

†Significance for a difference at α < 0.05.

‡There was a significant decrease in SBP from baseline to 9 months.

Hemodynamics and Systemic Metabolism 

Table 2 also lists the changes in hemodynamic measurements and metabolism after surgery. Concurrent with the decrease in blood pressure was a 33% reduction in the use of antihypertensive drugs at 3 and 9 months compared with baseline. A decrease in glucose, insulin, and leptin concentrations was observed early in the weight loss period, whereas the decrease in plasma FFA was apparent only at 9 months after surgery. The decrease in leptin correlated with the loss of weight from baseline to 3 months and 3 months to 9 months postoperatively (r=0.3, P=.03 and r=.64, P<.0001, respectively). Despite the greater decreases in leptin and fat mass early on, the correlation between the changes in leptin and fat mass was stronger later on (r=0.53, P=.001). Glucose and insulin concentrations rapidly decreased after surgery; thus, insulin sensitivity (homeostatic model of assessment for insulin sensitivity) began to normalize at 3 months or earlier (3 months was the first time point we assessed). The homeostatic model of assessment for insulin sensitivity continued to improve and was in the normal range by 9 months postoperatively (Table 2). This improvement in insulin sensitivity occurred despite the relatively small decreases in glucose and insulin concentrations at 9 months. It is a function of the nonlinear nature of the homeostatic model of assessment model.19

Echocardiography 

Left ventricular mass was increased compared with normal20 and decreased after 3 months of weight loss (Table 3). At baseline (ie, before surgery), 42% of the cohort exhibited left ventricular relaxation impairment based on tissue Doppler imaging (Ems) 21 with a mean velocity of 8.3 cm/sec (data not shown). There were no significant differences in any other baseline characteristics between those with diastolic dysfunction and those without (data not shown). Compared with baseline velocities, Ems increased at 3 months and 9 months after surgery (mean change [95% CI]: 1.9 cm/sec [0.52-3.4], P=.011 and 1.2 cm/sec [0.32-2.1]). Similar trends were seen with more load-dependent variables of diastolic function, such as early mitral inflow and deceleration time in the diastolic dysfunction group (Table 3).

Table 3. Echocardiographic Parameters
Baseline (SEM)Months 0 to 3 Mean Difference⁎Significance (P value)†Months to 3 to 9 Mean DifferenceSignificance (P value)†
LV Size
LVM/ht2.7(g/m2.7)49(2.3)3.0(−0.1-6.1)NS6.3(2.4-10.2)<.005
RWT(mm)42(0.9)0.3(−1.8-2.4)NS−0.2(−2.1-1.7)NS
Systolic Function
LVEF(%)63(1.4)1.2(−2.2-4.6)NS−2.1(−5.9-1.7)NS
FS(%)33(1.1)0.4(−1.8-2.7)NS−1.3(−4.4-1.9)NS
Sms(cm/sec)9.1(0.2)−0.1(−0.8-0.6)NS0.4(−0.3-1.1)NS
Diastolic Function
E(cm/sec)79(2.5)−16.0(−23.6-8.4)<.0001−11.0(−18.7-3.3)<.01
A(cm/sec)75(3.1)−3.2(−11.1-4.7)NS0.8(−6.5-8.0)NS
Deceleration time(msec)222(7.1)23.8(5.4-42.1)<.0519.1(−6.5-44.7)NS
Ems10(0.3)−0.4(−1.3-0.6)NS0.4(−0.4-1.1)NS

LV=left ventricle; LVEF=left ventricular ejection fraction; FS=fractional shortening; Sms=tissue Doppler systolic velocity; E=early mitral inflow velocity; A=late mitral inflow velocity; Ems=tissue Doppler diastolic velocity; LVM/ht2.7=left ventricular mass/height2.7; RWT=relative wall thickness; NS=not significant.

⁎Mean difference is a decrease in the outcome value unless indicated by a negative value.

†Significance for a difference at α < 0.05.

Histology 

Figure 1 shows oil-red-O stains of vastus lateralis biopsy samples at 0, 3, and 9 months after surgery. There was a significant decrease in oil-red-O staining at 9 months (4.2 arbitrary units [−2.4-10.9], P < .2, and 8.7 arbitrary units [2.4-15.1], P < .009, comparing baseline with 3 months, and 3 months with 9 months, respectively). The decrease in oil-red-O staining between 3 and 9 months correlated significantly with a decrease in weight and fat mass (r=0.57, P < .004; and r=0.44, P < .03, respectively). There also was a borderline association between oil-red-O intensity and plasma FFA levels (r=0.39, P < .059).

  • View full-size image.
  • Figure 1. 

    Oil-red-O stain of muscle biopsies. Samples were obtained at baseline and 3 and 9 months after surgery. The slides are representative of 4 sections for each patient at each of the time points (baseline and 3 and 9 months). Baseline versus 3 months 4.2 arbitrary units (−2.4-10.9; P<.2). Three months versus 9 months 8.7 arbitrary units (2.4-15.1; P<.009). See text for further details.

Skeletal Muscle Gene Expression 

Transcript levels for metabolic enzymes are shown in Figure 2. SCD transcript levels decreased dramatically at 3 months after surgery (Figure 2A) and remained so at 9 months. PDK-4 transcript levels also decreased rapidly and significantly at 3 months after surgery and continued to decrease at 9 months after surgery (Figure 2B). The expression of the PPAR-α–regulated genes (with the exception of PDK-4) only decreased 9 months postoperatively (Figure 2C), and the changes in the PPAR-α–regulated genes were highly correlative with each other (data not shown). These changes were concurrent with the decrease in the plasma FFA concentrations between 3 and 9 months postoperatively.

  • View full-size image.
  • Figure 2. 

    Transcript levels of metabolically relevant enzymes. A, mRNA levels of PDK4. *P < .0001 time point versus baseline. **P<.001, 3 months versus 9 months. B, mRNA levels of SCD1. *P<.0001, time point versus baseline. C, mRNA levels of PPAR-α–regulated genes. *P<.05, baseline versus 9 months; **P<.05, 3 months versus 9 months. PPAR-α=peroxisome proliferator activating receptor-α; CPT1=carnitine phosphatidyl transferase 1; MCAD=medium chain acetyl-CoA dehydrogenase. See text for further details.

Impact of the Type of Surgery on Outcomes 

The 2 types of surgery, laparoscopic small pound gastric bypass and LAGB, included in this study produce weight loss by different mechanisms; laparoscopic small pound gastric bypass is a restrictive and malabsorptive process, whereas LAGB is a restrictive process. We analyzed the outcomes for each group in this study to ascertain whether there was an effect produced by the surgery type. It is not surprising that there was a significant difference in the rate of weight loss between the 2 groups at both 3 and 9 months (mean weight loss at 3 and 9 months [standard error of the mean]: laparoscopic small pound gastric bypass 23 kg [1.9] and 20 kg [1.8], LAGB 15 kg [2.0] and 9 kg [2.8], P=.01 and .003, respectively, for 3 and 9 months). However, there was no significant contribution of the type of surgery to the overall improvement in weight by analysis of variance. Furthermore, there was no overall effect of the type of surgery on other outcomes measured, such as systemic metabolism, cardiac function, hemodynamics, or skeletal muscle gene expression (data not shown). These results suggest that outcomes in the early phase of weight loss are independent of the type of surgery.

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Discussion 

The main findings of our study are that weight loss induced by surgery is accompanied by a reversal of insulin resistance and dramatic changes in skeletal muscle metabolism. The former findings were expected, but the latter findings are new. Adipose tissue is an active endocrine organ, and an increased adipose mass is associated with insulin resistance and alterations of fatty acid oxidation by complex mechanisms.22, 23 These effects are mediated by adipose-derived hormones and cytokines (eg, leptin and tumor necrosis factor-α) that exert control over skeletal muscle metabolic gene expression. We speculate that the decrease in fat mass led to a decrease in leptin concentrations and to improvements in systemic insulin sensitivity. The most surprising findings were profound changes in skeletal muscle metabolic gene expression. Expression of SCD and PDK-4 decreased early in the weight loss process, whereas the PPAR-α–regulated gene expression decreased later in weight loss at the same time plasma FFA concentrations decreased. The changes may be responsible for the reversal of the maladaptive processes associated with obesity.

Skeletal Muscle Histology 

Oil-red-O stains, intra-myocellular triglycerides, and increased intensity suggests increased lipid storage in non-adipose tissue, most likely as the result of increased fatty acid supply, decreased rates of triglyceride export or hydrolysis, or decreased rates of fatty acid oxidation. The decrease in oil-red-O staining is associated with a normalization of substrate and hormone levels in the circulation and transcript levels in the tissue, suggesting a concerted program of reversed lipotoxicity.

Skeletal Muscle Gene Expression 

Other surprising findings were profound changes in skeletal muscle metabolic gene expression. Expression of SCD and PDK-4 decreased early in the weight-loss process, whereas the PPAR-α–regulated gene expression decreased later in weight loss at the same time plasma FFA concentrations decreased. This is the first demonstration of gene expression changes early after bariatric surgery. These changes have important implications for the possible mechanisms for the reversal of the maladaptive processes in non-adipose tissue.

The dramatic changes in transcript levels of steroyl-CoA desaturase (SCD) are especially relevant because SCD is the rate-limiting enzyme responsible for converting saturated fatty acids into monounsaturated fatty acids, the main precursors of triglycerides.24 SCD is known to be increased in the skeletal muscle of obese individuals and may lead to abnormal lipid partitioning.25 The marked decrease in SCD gene expression postoperatively suggests a change in the flux of fatty acid metabolism, moving from esterification toward beta-oxidation. This result is supported by a sustained expression of the key genes responsible for fatty acid oxidation, the PPAR-α–regulated genes, and the increased concentrations of plasma FFA. Leptin mediates lipid oxidation through the inhibition of SCD,26 which may result in an increase in saturated fatty acids and their oxidation.

Systemic glucose and insulin concentrations also decreased, resulting in improved systemic insulin sensitivity early in weight loss. As weight loss continued at 9 months after surgery, insulin sensitivity normalized in a majority of the cohort. Skeletal muscle gene expression of PDK-4 decreased by 83% from the baseline expression at 3 months and 92% at 9 months. PDK-4 phosphorylates the pyruvate dehydrogenase complex and is an important inhibitory regulator of glucose oxidation.27 PDK-4 is regulated by several factors, including insulin and fatty acid concentrations.28, 29

These findings are interesting because in the state of increased FFA concentrations or insulin resistance, PDK-4 expression is generally increased, limiting glucose oxidation. Our data at 3 months suggest a mechanism independent of systemic concentrations of FFA or insulin as the cause for the decreased expression of PDK-4. We suspect that the change is linked to improved insulin signaling, because there was no change in PPAR-α gene expression at this time point and PDK-4 expression has been shown to act independently of PPAR-α expression.30 Our findings are corroborated with another study demonstrating a decrease in PDK-4 expression 3 years after bilio-pancreatic diversion for weight loss.31

Left Ventricular Diastolic Function 

We speculate that the improvement in dysregulation of skeletal muscle metabolism also may have a correlate in improved function of cardiac muscle. Obesity is associated with derangements in left ventricular diastolic function.32 More important, diastolic dysfunction is an independent risk for increased morbidity and mortality.33, 34 We demonstrated an improvement in a load-independent measure of diastology, the septal mitral annular velocity, as measured by tissue Doppler imaging. Although we have previously demonstrated an inverse relationship between plasma FFA and diastolic function in obese individuals,35 in this study we were not able to demonstrate any significant correlations between the change in Ems and other measured outcomes. The inability to detect a relationship may be due to the small number of subjects in this cohort.

However, there are experimental data to suggest a role in FFA metabolism affecting left ventricular contractile function. Animal models of PPAR-α overexpression,36 as well as animals treated with PPAR agonists,37, 38 show evidence of cardiomyopathy and worsening heart failure. Furthermore, animal models of PPAR-α knockout demonstrate a cardioprotective phenotype compared with overexpression of PPAR-α.39 Diastolic function in our cohort shows an early and sustained improvement in those with dysfunction, and it is tempting to speculate that this change may be influenced by the improved FFA metabolism, influenced by leptin, SCD, and PPAR-α gene expression.

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Limitations 

We are excited about the findings, but we also are aware of the following limitations. First, this is a small prospective, longitudinal observational study, and we can only infer a relationship between the outcomes, not prove a causal relationship. Larger studies using external controls are needed to define the true relationships among skeletal muscle gene expression, systemic metabolism, and contractile function of the heart. Second, gene expression does not necessarily reflect protein content or activity. This is a shortcoming encountered in all gene expression studies, and further work is needed to establish metabolic, structural, and functional correlates.

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Conclusions 

Nonpharmacologic weight loss induced by bariatric surgery results in an early reversal of the maladaptive responses to obesity. Leptin resistance and insulin resistance reverse, leading to improved systemic metabolism and skeletal muscle gene expression. It is possible that these mechanisms also may exert a positive effect on left ventricular diastolic function. The implications of these findings for freedom from comorbidities of obesity remain to be substantiated by the long-term follow-up of the postsurgical patients.

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Acknowledgments 

The authors acknowledge the following contributors: Carol Wolin-Riklin, RN, University of Texas at Houston General Clinical Research Center, and Charles Majka, BS, University of Texas Houston Medical School for data collection; Rebecca L. Salazar, BS, University of Texas Houston Medical School Department of Medicine, for technical assistance. We thank Roxy A. Tate for expert editorial help.

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 Supported by the National Heart, Lung, and Blood Institute of the US Public Health Service (R01HL73162 and M01 RR02558). None of the authors of this work have any financial conflicts of interest to disclose. All authors had access to the data and a role in writing the article.

 Clinical Trials Registry: ClinicalTrials.gov Identifier: NCT00178633; http:/www.clinicaltrials.gov

PII: S0002-9343(08)00756-0

doi:10.1016/j.amjmed.2008.06.033

The American Journal of Medicine
Volume 121, Issue 11 , Pages 966-973, November 2008

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