Effect of Bariatric Weight Loss on the Adipose Lipolytic Transcriptome in Obese Humans

Karki, Shakun; Farb, Melissa G.; Myers, Samantha; Apovian, Caroline; Hess, Donald T.; Gokce, Noyan

doi:https://doi.org/10.1155/2015/106237

Mediators of Inflammation

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Volume 2015 | Article ID 106237 | https://doi.org/10.1155/2015/106237

Effect of Bariatric Weight Loss on the Adipose Lipolytic Transcriptome in Obese Humans

Shakun Karki,¹Melissa G. Farb,¹Samantha Myers,¹Caroline Apovian,¹Donald T. Hess,²and Noyan Gokce¹

Academic Editor: Aaron L. Sverdlov

Received23 Jul 2015

Accepted02 Nov 2015

Published18 Nov 2015

Abstract

Background. Dysregulated lipolysis has been implicated in mechanisms of cardiometabolic disease and inflammation in obesity. Purpose. We sought to examine the effect of bariatric weight loss on adipose tissue lipolytic gene expression and their relationship to systemic metabolic parameters in obese subjects. Methods/Results. We biopsied subcutaneous adipose tissue in 19 obese individuals (BMI 42 ± 5 kg/m², 79% female) at baseline and after a mean period of 8 ± 5 months (range 3–15 months) following bariatric surgery. We performed adipose tissue mRNA expression of proteins involved in triglyceride hydrolysis and correlated their weight loss induced alterations with systemic parameters associated with cardiovascular disease risk. mRNA transcripts of adipose triglyceride lipase (ATGL), hormone-sensitive lipase (HSL), and lipid droplet proteins comparative gene identification 58 (CGI-58) and perilipin increased significantly after weight loss ( for all). ATGL expression correlated inversely with plasma triglyceride (TG), hemoglobin A1C (HbA1C), and glucose, and HSL expression correlated negatively with glucose, while CGI-58 was inversely associated with HbA1C. Conclusion. We observed increased expression of adipose tissue lipolytic genes following bariatric weight loss which correlated inversely with systemic markers of lipid and glucose metabolism. Functional alterations in lipolysis in human adipose tissue may play a role in shaping cardiometabolic phenotypes in human obesity.

1. Introduction

Obesity and its associated widespread metabolic abnormalities such as insulin resistance and dyslipidemia have emerged as major public health problems worldwide [1, 2]. Among the multiple mechanisms responsible for mediating obesity-related cardiovascular disease is the upregulated concentrations of circulating free-fatty acids (FFA) that have been associated with insulin resistance and inflammation [3–5]. Fatty acids play important physiological roles in energy metabolism while also serving as signaling molecules, and their mobilization from triglycerides (TG) is regulated by specific hydrolytic lipases including adipose triglyceride lipase (ATGL) and hormone-sensitive lipase (HSL), as well as lipid droplet proteins comparative gene identification protein 58 (CGI-58) and perilipin.

Experimental studies suggest that functional alterations in the enzymatic activity of lipases under obese conditions may lead to dysregulated FFA metabolism. ATGL protein and mRNA are downregulated in mouse models of obesity [6]. Overexpression of ATGL specific to adipose tissue promotes fatty acid use and attenuates diet-induced obesity [7], while ATGL deficiency leads to changes in insulin signaling and ectopic fat accumulation in nonadipose tissue [8–10]. However, expression of lipases in human obesity is incompletely studied [11–13]. One report demonstrated that both lean and obese subjects express comparable amounts of ATGL protein while HSL is attenuated in obesity [11]. Conversely, another study suggested that although obese subjects express significantly high ATGL mRNA, protein expression is reduced. Moreover, they reported that HSL mRNA was upregulated in visceral but not subcutaneous fat in obesity [12]. Another investigation observed significant reductions in both ATGL and HSL mRNA and protein in obese insulin resistant subjects, and weight loss by hypocaloric diets induced decreases in ATGL and HSL expression [13]. The literature thus demonstrates variable transcriptomic signatures in largely cross-sectional comparisons between different groups of individuals, and limited data are available on longitudinal effects of weight reduction.

Bariatric surgery is currently the most effective and durable method for sustained weight loss and cardiometabolic benefit for the treatment of obesity [14–16]. In the present study, we sought to examine the effect of bariatric surgery on adipose tissue expression of lipolytic enzymes before and after extensive weight loss in obese humans and determine whether tissue changes associate with systemic markers of whole body metabolism.

2. Materials and Methods

2.1. Study Subjects

Consecutive obese men and women (BMI ≥ 35 kg/m², age ≥ 18 years) with long-standing obesity enrolled in the Boston Medical Center Bariatric Surgery Program were recruited into the study. Subcutaneous adipose tissue samples at baseline were collected intraoperatively from the lower abdominal wall during planned bariatric surgery, as previously described [17–19]. Follow-up fat tissue biopsy was performed percutaneously via periumbilical punch and needle biopsy of subcutaneous fat during a postoperative follow-up visit. The subcutaneous depot that is sampled intraoperatively is the same anatomic layer that is accessed in our follow-up transcutaneous biopsy. Each subject provided two biopsy specimens from the subcutaneous depot, one at baseline and one during the postoperative visit. All biopsies were performed under fasting conditions. Subjects with unstable medical conditions such as active coronary syndromes, congestive heart failure, systemic infection, acute illness, malignancy, or pregnancy were excluded. The study was approved by the Boston University Medical Center Institutional Review Board and written consent was obtained from all participants.

2.2. Percutaneous Adipose Tissue Biopsy

For follow-up adipose tissue biopsies, subjects were placed in supine position with sterile draping of the abdominal region. Local skin anesthesia was performed with subcutaneous lidocaine injection and a small superficial 0.5 cm skin incision made lateral to the umbilicus with a tiny scalpel which allows for both aspiration of fat using a large-bore cannula and several punch biopsies and/or manual debridement of tissue below the skin layer, providing specimens of intact adipose tissue. The anatomic layer and qualitative yield of this procedure are the same as the intraoperative baseline collection. The superficial skin incision was then closed with self-absorbing sutures and biopsy sites were inspected in follow-up clinic within 1 week.

2.3. Anthropometric and Biochemical Measures

During a presurgical outpatient and subsequent postoperative follow-up visit, clinical characteristics including blood pressure, height, weight, body mass index (BMI), and waist circumference were measured, and cardiovascular risk factors were recorded. Fasting blood was taken via an antecubital vein for biochemical measures including lipids, glucose, insulin, glycosylated hemoglobin (HbA1c), high-sensitivity CRP (hs-CRP), and homeostasis model assessment (HOMA) as the index of insulin sensitivity. All biochemical analyses were performed by the Boston Medical Center clinical chemistry laboratory.

2.4. Adipose Tissue Gene Expression

Immediately following adipose tissue collection, tissue samples were stored in RNAlater (Sigma Aldrich) solution at −80°C. Total RNAs were isolated from homogenized whole adipose tissues using the QIAzol reagent and RNeasy Mini kits (Qiagen, Germantown, MD). RNA (0.5–1.5 μg) was retrotranscribed with High Capacity cDNA Synthesis Kits (Life Technologies). Quantitative real time PCR reactions were performed using TaqMan gene expression assays in a ViiA7 PCR system (Life Technologies). Results were analyzed with the ΔΔCt method using GAPDH as a reference.

2.5. Statistics

Clinical characteristics of subjects were analyzed using SPSS 20.0 and presented as mean ± SD or percentage. All other analyses were performed using GraphPad Prism 6.0 software. Differences in clinical characteristics and gene expression between baseline and follow-up visits were examined using Student’s paired -tests. Spearman correlation analysis was performed to examine associations between lipolytic gene expression and clinical parameters which were normally distributed. A value of was accepted as statistically significant. Graphic data are presented as mean ± SEM unless otherwise indicated.

3. Results

3.1. Clinical Characteristics

A total of 19 obese (BMI kg/m², 79% female) subjects were enrolled and followed longitudinally for a mean period of months (range 3–15 months) after bariatric surgery. Table 1 displays the clinical characteristics of subjects at baseline and after weight loss. As expected, bariatric intervention produced a significant 25% weight decline for the entire group. This was associated with significant decreases in BMI, waist circumference, HbA1c, triglycerides, HOMA-IR, insulin, glucose levels, and prevalent hypertension. Additionally, there was a marked decrease in hs-CRP as a marker of systemic inflammation with >5-fold decline following bariatric surgery.

3.2. Adipose Tissue Gene Expression

As shown in Figure 1, relative mRNA expression of ATGL (a), HSL (b), CGI-58 (c), and perilipin (d) significantly increased after weight loss surgery compared to baseline, with greatest relative increase observed for perilipin.

(a)

(b)

(c)

(d)

3.3. Correlations between Lipolytic Gene Expression and Clinical Parameters

Plasma concentration of TG (Figure 2(a)), HbA1C (Figure 2(b)), and glucose (Figure 2(c)) correlated negatively with ATGL mRNA expression after weight loss. In addition, plasma glucose was inversely associated with HSL mRNA (Figure 3(a)), with a similar finding trending for HbA1C (, data not displayed). Gene expression of CGI-58 gene was inversely correlated with plasma HbA1C after weight loss (Figure 3(b)). We found no correlations between adipose gene expression and clinical parameters at baseline (data not displayed).

(a)

(b)

(c)

(a)

(b)

4. Discussion

In the present study, we longitudinally examined the effect of surgical weight loss on subcutaneous adipose tissue transcripts of lipases and lipid droplet proteins involved in triglyceride hydrolysis and metabolism in obese humans. mRNA transcripts of ATGL, HSL, CGI-58, and perilipin significantly increased following weight loss, and their expression correlated inversely with systemic metabolic parameters including plasma triglycerides, glucose, and HbA1C. These findings suggest that weight decline is associated with lipolytic alterations that are detectable in human adipose tissue and are linked to processes that may regulate systemic metabolism.

Adipose tissue serves as an energy reservoir that modulates triglyceride clearance and FFA release in response to whole body metabolic requirements. Under conditions of obesity and positive energy balance, fat accumulates in both adipose tissue and ectopic organs and is associated with the development of dyslipidemia, insulin resistance, and inflammation in both animal models and humans [17, 20–23] which increase cardiovascular disease risk. These processes may involve dysregulation of several enzymes including ATGL and HSL and cofactors. Although the published literature is mixed on the relative expression of ATGL in human adipose tissue in obesity [11–13, 24], we demonstrated consistent increases in expression following weight loss which suggests downregulation under obese conditions. Weight decline would presumably stimulate lipolysis and thus increase enzymatic activity in human fat stores. Moreover, we observed that this process is associated with improved insulin resistance possibly owing to decreased FFA flux, as ATGL has been linked with increased insulin sensitivity [25] and increased plasma FFA mobilization [26].

Data on HSL activity and expression in obesity have also been mixed. There are reports of decreased HSL lipolytic activity with obesity [11], and possible gender differences with decreased or unaltered HSL protein with weight loss [27, 28]. We now demonstrate consistent increases in HSL mRNA, as with ATGL, following weight loss which correlated inversely with plasma glucose. We also observed upregulation of perilipin and CGI-58 which represent key proteins associated with intracellular lipid droplets. Mutations in CGI-58 in animal models lead to deficient catabolism of cellular triacylglycerol and promote lipid accumulation in nonadipose tissue [29]. Moreover, patients with mutations in CGI-58 exhibit defective lipolysis and ectopic lipid accumulation in multiple tissues [30]. It is believed that efficient ATGL activity requires CGI-58 which associates with lipid droplets and interacts with perilipin that modulates droplet turnover [31]. Our observation of a coordinate upregulation of all four measured transcripts associated with lipolysis and lipid droplets following weight loss suggests that their activities may be interlinked for effective triglyceride hydrolysis and consequently whole body metabolism, as supported by significant correlations with systemic measures of triglyceride and glucose handling.

In the present study, we also observed a remarkable decline in plasma hs-CRP which has been described previously in association with weight loss [32, 33]. It is well established that obesity is associated with a chronic, subclinical degree of inflammation that is derived in part from macrophage-driven adipose tissue inflammation in response to several pathological tissue changes including adipocyte hypertrophy [21, 34]. Local overproduction of FFA may also represent a mediator for immune activation [3, 4, 35, 36] and our observation of reduced inflammation with weight loss may be related, in part, to decreased FFA following weight loss as previously established [37, 38], although this was not specifically measured in this study.

There are several limitations to our study. The sample size is relatively small and experimental design was limited to a surgical population undergoing bariatric surgery and thus findings may not be applicable to the general population or lesser degrees of obesity. However, our demonstration of significant clinical correlations even with this small sample makes our results more compelling. Moreover, our findings are limited to the subcutaneous depot. We acknowledge that the visceral depot may be more metabolically active compared to subcutaneous one; however sequential visceral biopsies are not possible since a repeat invasive abdominal operation would be required which is not justifiable for only research purposes. However, we believe that much can be learned from examining longitudinal changes in the subcutaneous fat of obese individuals. Additionally, we acknowledge that methods for collecting fat samples at baseline and follow-up biopsy were different and may have affected gene expression; however we believe that the techniques which are all performed under fasting conditions are comparable. We did not measure protein levels or examine functional activity of these enzymes; thus observations are limited to mRNA expression patterns; however protein tracked mRNA transcripts in a prior study [13]. Lastly, our study design does not enable us to distinguish between the effect of negative energy balance and the effect of weight loss on changes in gene expression and clinical parameters. These limitations are counterbalanced by our ability to study the same subjects longitudinally by examining the effect of major weight loss and studying changes in adipose tissue that may provide clues to mechanisms of systemic disease.

In conclusion, we observed increased expression of adipose tissue lipolytic genes which correlated inversely with systemic markers of lipid and glucose metabolism following bariatric weight loss. Functional alterations in lipolytic activity in human adipose tissue may play important roles in shaping systemic phenotypes associated with cardiovascular risk factors in human obesity.

Conflict of Interests

The authors declare that there is no conflict of interests regarding the publication of this paper.

Acknowledgments

The authors thank Dr. Michael P. Lavalley, Ph.D., for his statistical input and Dr. Maria Zuriaga Herrero, Ph.D., for her assistance with RT-PCR. Dr. Noyan Gokce is supported by National Institutes of Health (NIH) Grants HL081587, HL126141, and HL114675. Dr. Karki is supported by NIH Grant T32 HL07224.

References

K. M. Flegal, D. Carroll, B. K. Kit, and C. L. Ogden, “Prevalence of obesity and trends in the distribution of body mass index among US adults, 1999–2010,” The Journal of the American Medical Association, vol. 307, no. 5, pp. 491–497, 2012.
View at: Publisher Site | Google Scholar
G. Whitlock, S. Lewington, P. Sherliker et al., “Body-mass index and cause-specific mortality in 900 000 adults: collaborative analyses of 57 prospective studies,” The Lancet, vol. 373, no. 9669, pp. 1083–1096, 2009.
View at: Publisher Site | Google Scholar
H. Shi, M. V. Kokoeva, K. Inouye, I. Tzameli, H. Yin, and J. S. Flier, “TLR4 links innate immunity and fatty acid-induced insulin resistance,” The Journal of Clinical Investigation, vol. 116, no. 11, pp. 3015–3025, 2006.
View at: Publisher Site | Google Scholar
W. L. Holland, B. T. Bikman, L.-P. Wang et al., “Lipid-induced insulin resistance mediated by the proinflammatory receptor TLR4 requires saturated fatty acid-induced ceramide biosynthesis in mice,” The Journal of Clinical Investigation, vol. 121, no. 5, pp. 1858–1870, 2011.
View at: Publisher Site | Google Scholar
D. B. Savage, K. F. Petersen, and G. I. Shulman, “Disordered lipid metabolism and the pathogenesis of insulin resistance,” Physiological Reviews, vol. 87, no. 2, pp. 507–520, 2007.
View at: Publisher Site | Google Scholar
P. Oliver, A. Caimari, R. Díaz-Rúa, and A. Palou, “Diet-induced obesity affects expression of adiponutrin/PNPLA3 and adipose triglyceride lipase, two members of the same family,” International Journal of Obesity, vol. 36, no. 2, pp. 225–232, 2012.
View at: Publisher Site | Google Scholar
M. Ahmadian, R. E. Duncan, K. A. Varady et al., “Adipose overexpression of desnutrin promotes fatty acid use and attenuates diet-induced obesity,” Diabetes, vol. 58, no. 4, pp. 855–866, 2009.
View at: Publisher Site | Google Scholar
R. Zimmermann, A. Lass, G. Haemmerle, and R. Zechner, “Fate of fat: the role of adipose triglyceride lipase in lipolysis,” Biochimica et Biophysica Acta—Molecular and Cell Biology of Lipids, vol. 1791, no. 6, pp. 494–500, 2009.
View at: Publisher Site | Google Scholar
P. C. Kienesberger, D. Lee, T. Pulinilkunnil et al., “Adipose triglyceride lipase deficiency causes tissue-specific changes in insulin signaling,” The Journal of Biological Chemistry, vol. 284, no. 44, pp. 30218–30229, 2009.
View at: Publisher Site | Google Scholar
G. Haemmerle, A. Lass, R. Zimmermann et al., “Defective lipolysis and altered energy metabolism in mice lacking adipose triglyceride lipase,” Science, vol. 312, no. 5774, pp. 734–737, 2006.
View at: Publisher Site | Google Scholar
M. Rydén, J. Jocken, V. Van Harmelen et al., “Comparative studies of the role of hormone-sensitive lipase and adipose triglyceride lipase in human fat cell lipolysis,” The American Journal of Physiology—Endocrinology and Metabolism, vol. 292, no. 6, pp. E1847–E1855, 2007.
View at: Publisher Site | Google Scholar
G. R. Steinberg, B. E. Kemp, and M. J. Watt, “Adipocyte triglyceride lipase expression in human obesity,” American Journal of Physiology—Endocrinology and Metabolism, vol. 293, no. 4, pp. E958–E964, 2007.
View at: Publisher Site | Google Scholar
J. W. E. Jocken, D. Langin, E. Smit et al., “Adipose triglyceride lipase and hormone-sensitive lipase protein expression is decreased in the obese insulin-resistant state,” Journal of Clinical Endocrinology and Metabolism, vol. 92, no. 6, pp. 2292–2299, 2007.
View at: Publisher Site | Google Scholar
L. Sjöström, M. Peltonen, P. Jacobson et al., “Bariatric surgery and long-term cardiovascular events,” The Journal of the American Medical Association, vol. 307, no. 1, pp. 56–65, 2012.
View at: Publisher Site | Google Scholar
S. J. Bigornia, M. G. Farb, S. Tiwari et al., “Insulin status and vascular responses to weight loss in obesity,” Journal of the American College of Cardiology, vol. 62, no. 24, pp. 2297–2305, 2013.
View at: Publisher Site | Google Scholar
M. D. Jensen, D. H. Ryan, C. M. Apovian et al., “2013 AHA/ACC/TOS guideline for the management of overweight and obesity in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and The Obesity Society,” Journal of the American College of Cardiology, vol. 63, no. 25, part B, pp. 2985–3023, 2014.
View at: Publisher Site | Google Scholar
M. G. Farb, S. Bigornia, M. Mott et al., “Reduced adipose tissue inflammation represents an intermediate cardiometabolic phenotype in obesity,” Journal of the American College of Cardiology, vol. 58, no. 3, pp. 232–237, 2011.
View at: Publisher Site | Google Scholar
D. T. Ngo, M. G. Farb, R. Kikuchi et al., “Antiangiogenic actions of vascular endothelial growth factor-A165b, an inhibitory isoform of vascular endothelial growth factor-A, in human obesity,” Circulation, vol. 130, no. 13, pp. 1072–1080, 2014.
View at: Publisher Site | Google Scholar
S. Karki, M. G. Farb, D. T. Ngo et al., “Forkhead box O-1 modulation improves endothelial insulin resistance in human obesity,” Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 35, no. 6, pp. 1498–1506, 2015.
View at: Publisher Site | Google Scholar
H. Xu, G. T. Barnes, Q. Yang et al., “Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance,” Journal of Clinical Investigation, vol. 112, no. 12, pp. 1821–1830, 2003.
View at: Publisher Site | Google Scholar
S. P. Weisberg, D. McCann, M. Desai, M. Rosenbaum, R. L. Leibel, and A. W. Ferrante Jr., “Obesity is associated with macrophage accumulation in adipose tissue,” Journal of Clinical Investigation, vol. 112, no. 12, pp. 1796–1808, 2003.
View at: Publisher Site | Google Scholar
D. A. Gutierrez, M. J. Puglisi, and A. H. Hasty, “Impact of increased adipose tissue mass on inflammation, insulin resistance, and dyslipidemia,” Current Diabetes Reports, vol. 9, no. 1, pp. 26–32, 2009.
View at: Publisher Site | Google Scholar
G. I. Shulman, “Ectopic fat in insulin resistance, dyslipidemia, and cardiometabolic disease,” The New England Journal of Medicine, vol. 371, no. 12, pp. 1131–1141, 2014.
View at: Publisher Site | Google Scholar
T. S. Nielsen, M. H. Vendelbo, N. Jessen et al., “Fasting, but not exercise, increases adipose triglyceride lipase (ATGL) protein and reduces G(0)/G(1) switch gene 2 (G0S2) protein and mRNA content in human adipose tissue,” Journal of Clinical Endocrinology and Metabolism, vol. 96, no. 8, pp. E1293–E1297, 2011.
View at: Publisher Site | Google Scholar
A. Yao-Borengasser, V. Varma, R. H. Coker et al., “Adipose triglyceride lipase expression in human adipose tissue and muscle. Role in insulin resistance and response to training and pioglitazone,” Metabolism, vol. 60, no. 7, pp. 1012–1020, 2011.
View at: Publisher Site | Google Scholar
S. Schenk, M. P. Harber, C. R. Shrivastava, C. F. Burant, and J. F. Horowitz, “Improved insulin sensitivity after weight loss and exercise training is mediated by a reduction in plasma fatty acid mobilization, not enhanced oxidative capacity,” Journal of Physiology, vol. 587, no. 20, pp. 4949–4961, 2009.
View at: Publisher Site | Google Scholar
S. Klein, S. Klein, K. Luu et al., “Effect of weight loss on whole body and cellular lipid metabolism in severely obese humans,” The American Journal of Physiology—Endocrinology and Metabolism, vol. 270, no. 5, pp. E739–E745, 1996.
View at: Google Scholar
M. Kolehmainen, H. Vidal, J. J. Ohisalo, E. Pirinen, E. Alhava, and M. I. J. Uusitupa, “Hormone sensitive lipase expression and adipose tissue metabolism show gender difference in obese subjects after weight loss,” International Journal of Obesity, vol. 26, no. 1, pp. 6–16, 2002.
View at: Publisher Site | Google Scholar
K. A. Zierler, D. Jaeger, N. M. Pollak et al., “Functional cardiac lipolysis in mice critically depends on comparative gene identification-58,” The Journal of Biological Chemistry, vol. 288, no. 14, pp. 9892–9904, 2013.
View at: Publisher Site | Google Scholar
A. Lass, R. Zimmermann, G. Haemmerle et al., “Adipose triglyceride lipase-mediated lipolysis of cellular fat stores is activated by CGI-58 and defective in Chanarin-Dorfman Syndrome,” Cell Metabolism, vol. 3, no. 5, pp. 309–319, 2006.
View at: Publisher Site | Google Scholar
J. G. Granneman, H.-P. H. Moore, R. Krishnamoorthy, and M. Rathod, “Perilipin controls lipolysis by regulating the interactions of AB-hydrolase containing 5 (Abhd5) and adipose triglyceride lipase (Atgl),” Journal of Biological Chemistry, vol. 284, no. 50, pp. 34538–34544, 2009.
View at: Publisher Site | Google Scholar
A. Tchernof, A. Nolan, C. K. Sites, P. A. Ades, and E. T. Poehlman, “Weight loss reduces C-reactive protein levels in obese postmenopausal women,” Circulation, vol. 105, no. 5, pp. 564–569, 2002.
View at: Publisher Site | Google Scholar
L. M. Belalcazar, D. M. Reboussin, S. M. Haffner et al., “A 1-year lifestyle intervention for weight loss in individuals with type 2 diabetes reduces high C-reactive protein levels and identifies metabolic predictors of change: from the Look AHEAD (Action for Health in Diabetes) study,” Diabetes Care, vol. 33, no. 11, pp. 2297–2303, 2010.
View at: Publisher Site | Google Scholar
M. Pasarica, O. R. Sereda, L. M. Redman et al., “Reduced adipose tissue oxygenation in human obesity: evidence for rarefaction, macrophage chemotaxis, and inflammation without an angiogenic response,” Diabetes, vol. 58, no. 3, pp. 718–725, 2009.
View at: Publisher Site | Google Scholar
C. Klein-Platat, J. Drai, M. Oujaa, J.-L. Schlienger, and C. Simon, “Plasma fatty acid composition is associated with the metabolic syndrome and low-grade inflammation in overweight adolescents,” American Journal of Clinical Nutrition, vol. 82, no. 6, pp. 1178–1184, 2005.
View at: Google Scholar
R. Belfort, L. Mandarino, S. Kashyap et al., “Dose-response effect of elevated plasma free fatty acid on insulin signaling,” Diabetes, vol. 54, no. 6, pp. 1640–1648, 2005.
View at: Publisher Site | Google Scholar
K. A. Varady, V. T. Dam, M. C. Klempel et al., “Effects of weight loss via high fat vs. low fat alternate day fasting diets on free fatty acid profiles,” Scientific Reports, vol. 5, article 7561, 2015.
View at: Publisher Site | Google Scholar
M. Raffaelli, A. Iaconelli, G. Nanni et al., “Effects of biliopancreatic diversion on diurnal leptin, insulin and free fatty acid levels,” British Journal of Surgery, vol. 102, no. 6, pp. 682–690, 2015.
View at: Publisher Site | Google Scholar

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Copyright © 2015 Shakun Karki et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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