Impact of gut hormone FGF-19 on type-2 diabetes and mitochondrial recovery in a prospective study of obese diabetic women undergoing bariatric surgery
© The Author(s). 2017
Received: 6 October 2016
Accepted: 18 January 2017
Published: 16 February 2017
The ileal-derived hormone, fibroblast growth factor 19 (FGF-19), may promote weight loss and facilitate type-2 diabetes mellitus remission in bariatric surgical patients. We investigated the effect of different bariatric procedures on circulating FGF-19 levels and the resulting impact on mitochondrial health in white adipose tissue (AT).
Obese and type-2 diabetic women (n = 39, BMI > 35 kg/m2) undergoing either biliopancreatic diversion (BPD), laparoscopic greater curvature plication (LGCP), or laparoscopic adjustable gastric banding (LAGB) participated in this ethics approved study. Anthropometry, biochemical, clinical data, serum, and AT biopsies were collected before and 6 months after surgery. Mitochondrial gene expression in adipose biopsies and serum FGF-19 levels were then assessed.
All surgeries led to metabolic improvements with BPD producing the greatest benefits on weight loss (↓30%), HbA1c (↓28%), and cholesterol (↓25%) reduction, whilst LGCP resulted in similar HbA1c improvements (adjusted for BMI). Circulating FGF-19 increased in both BPD and LGCP (χ2(2) = 8.088; P = 0.018), whilst, in LAGB, FGF-19 serum levels decreased (P = 0.028). Interestingly, circulating FGF-19 was inversely correlated with mitochondrial number in AT across all surgeries (n = 39). In contrast to LGCP and LAGB, mitochondrial number in BPD patients corresponded directly with changes in 12 of 14 mitochondrial genes assayed (P < 0.01).
Elevated serum FGF-19 levels post-surgery were associated with improved mitochondrial health in AT and overall diabetic remission. Changes in circulating FGF-19 levels were surgery-specific, with BPD producing the best metabolic outcomes among the study procedures (BPD > LGCP > LAGB), and highlighting mitochondria in AT as a potential target of FGF-19 during diabetes remission.
KeywordsGut hormone FGF-19 Mitochondria Type-2 diabetes recovery Obesity Bariatric surgery
A key factor in the development of type-2 diabetes and metabolic syndrome is the inability of adipose tissue (AT) to cope with the chronic insult of over-nutrition, whilst maintaining important metabolic and endocrine functions [1, 2]. At the forefront of this challenging environment are mitochondria, major nutrient sensors and metabolic regulators, which are fundamental to AT function [3, 4]. However, during sustained conditions of chronic nutrient excess, such as obesity and type-2 diabetes, mitochondria appear unable to cope well with this environment, leading to fragmentation, unresponsiveness and dysfunction [5–7]. This nutrient-induced mitochondrial dysfunction can lead to impaired respiration, lipotoxicity, oxidative species accumulation and inflammation, further exacerbating insulin resistance and type-2 diabetes [8–13]. Indeed, the importance of adequate mitochondrial function for metabolic health is further highlighted by the observation that mitochondrial DNA mutations often result in diabetic phenotypes [14–16].
Both insulin resistance and type-2 diabetes status can be reversed through bariatric surgery, with significantly greater success rates than pharmacological, exercise and diet interventions [17–19]. Depending on the procedure, bariatric surgery involves a type/degree of gastro-intestinal remodelling, which can lead to reduced stomach volume and nutrient absorption capacity [20, 21]; however, this alone cannot fully explain the profound weight loss and metabolic improvement observed after these surgeries versus medical/lifestyle interventions .
Recently, the ileal-derived hormone, fibroblast growth factor 19 (FGF-19), has been identified as a novel enterokine regulator of glucose and lipid homeostasis, which is potentially involved in metabolic recovery following bariatric surgery . Indeed, rodent studies have shown that mice lacking the receptor required for gut secretion of FGF-19 show significantly impaired weight loss and glucose improvement following bariatric surgery compared with their wild-type counterparts . In addition, direct administration of recombinant FGF-15 (FGF-19 in humans) to obese mice leads to significant weight reduction, principally AT reduction, and reverses dietary and leptin-deficient diabetes . Moreover, in humans, data from clinical studies would seemingly indicate FGF-19 as a cause rather than consequence of type-2 diabetes improvement, given that neither lifestyle interventions nor intense medical management of type-2 diabetes appears to increase circulating FGF-19 levels, despite similar reductions in HbA1c to surgical procedures . However, there is good clinical evidence that certain bariatric procedures increase serum FGF-19 levels [27–30]. As such, both human and rodent studies suggest that increased circulating FGF-19 levels may contribute to the underlying mechanisms of metabolic improvement following certain types of bariatric surgery.
Beyond the potential effects on white AT, studies have shown FGF-19 to exert several advantageous effects on various metabolic relevant organs . In the central nervous system, FGF-19 has been associated with lowered brain-hedonistic responses, reduced food intake, improved glycaemic control and enhanced glucose effectiveness [31, 32]. Furthermore, in the liver, FGF-19 has been shown to increase energy expenditure and fatty acid oxidation through raised delivery of fatty acids to the mitochondria . Additionally, in brown AT, elevated FGF-19 (either through genetic over-expression or systemic administration) can affect the metabolic rate and activity of this highly energy-consuming tissue [25, 33]. These studies also stress the importance of mitochondria as a target of FGF-19 [25, 31–33], although its role in white AT mitochondria, particularly within the context of type-2 diabetes, remains largely unknown. Therefore, in the present study, we investigated the hypothesis that changes in serum FGF-19 levels after bariatric surgery support metabolic recovery via improvement in mitochondrial function within white AT.
Ethics and study design
The study was approved by the Ethics Committee of the Institute of Endocrinology (Institute of Endocrinology, Ethics Committee EC: 19/5/2009, Prague, Czech Republic). All study participants provided written and informed consent in accordance with the Declaration of Helsinki. Thirty-nine morbidly obese (BMI > 35 kg/m2), type-2 diabetic, Caucasian women undergoing either biliopancreatic diversion (BPD; n = 12), laparoscopic greater curvature plication (LGCP; n = 15), or laparoscopic adjustable gastric banding (LAGB; n = 12) at the OB clinic, Prague, Czech Republic, were recruited to participate in this study. Thorough biochemical and anthropometric investigations were conducted before (baseline) and at 6 months after surgery with collection of serum samples and abdominal subcutaneous white AT biopsies at both of these time points. Patients on pharmacological treatment with incretin mimetics and/or insulin were not included in this study.
Blood biochemistry and body composition analysis
All anthropometric and biochemical measurements were performed before and 6 months after surgery. Following a 10-hour overnight fast, venous blood was sampled in all patients, collected in chilled EDTA-containing tubes with and without aprotinin (for glucose and insulin measurements), aliquoted and frozen at –80 °C until assayed. Serum glucose, HbA1c and lipids were determined using the Cobas 6000 analyzer. Insulin resistance was assessed using the homeostatic model assessment of insulin resistance (HOMA-IR) according to the following equation: HOMA-IR = fasting glucose (mmol/L) × fasting insulin (mIU/L)/22.5, as previously described . The Friedwald formula  was employed to compute serum levels of LDL cholesterol. Body weight was measured to the nearest 0.5 kg and height to the nearest 1 cm. Percentage excess weight loss was calculated according to the following equation: (preoperative weight-postoperative weight/preoperative weight-ideal body weight) × 100, and body fat mass was measured using the bioimpedance method (Tanita TBF-300; Tanita corporation).
RNA isolation and qRT-PCR
For RNA extraction, 100 mg of frozen AT was homogenized in 500 μL Qiazol reagent (#79306 Qiagen, UK) then isolated using a column-based isolation method (RNeasy Lipid Tissue Mini Kit; #74804 Qiagen, UK) according to manufacturer’s instructions. Samples were digested with DNase I to remove potential genomic DNA contaminants (DNase I kit, #AMP-D1 Sigma-Aldrich). RNA was eluted in 10 μL RNase-free water and 1 μL quantified in duplicate using a spectrophotometer (Nanodrop ND-1000, labtech) at 260 nm absorbancy. Synthesis of cDNA was performed using 200 ng RNA per sample and a Bioline mRNA reverse transcription kit (#BIO-65026) according to the manufacturer’s instructions. Gene expression was assayed through quantitative real-time polymerase chain reaction (qRT-PCR) using ABI 7500 standard sequence detection system (Applied Biosystems, UK). Each reaction was prepared to 25 μL final volume containing Taqman Universal PCR mastermix (#4304437 Applied Biosystems, UK), 1 μL sample cDNA and a specific commercially available Taqman gene expression assay (Applied Biosystems, UK; PGC1α, Hs00173304_m1; POLG, Hs01018668_m1; TFAM, Hs00273372_s1; mtND6, Hs02596879_g1; SDHA, Hs00188166_m1; COX4I1, Hs00971639_m1; mtATP6, Hs02596862_g1; UCP2, Hs01075227_m1; SOD1, Hs00533490_m1; SOD2, Hs00167809_m1; MFN2, Hs00208382_m1; OPA1, Hs01047018_m1; DRP1, Hs01552605_m1; FIS1, Hs00211420_m1). All samples were assayed in triplicate and multiplexed using 18S (ribosomal RNA) as a pre-optimised control probe. As per the manufacturer’s instructions, reactions were carried out at 50 °C for 2 minutes, 95 °C for 10 minutes, and then 40 cycles of 95 °C for 15 seconds and 60 °C for 1 min. For data analysis, a ΔCt was calculated based on the difference between 18S and the target gene. Gene expression was calculated based on the following formula: mRNA expression = 2–ΔΔCt, where ΔCt = target gene – 18S.
Evaluation of mitochondrial number
Total DNA was extracted from 50 mg frozen AT samples using DNeasy Blood and Tissue Mini Kit (#69504 Qiagen, UK) in accordance to the manufacturer’s instructions. RNase treatment was performed to eliminate possible RNA contamination. DNA was eluted with 100 μL AE buffer and quantified using a spectrophotometer (Nanodrop ND-1000, Labtech). Relative amounts of mitochondrial DNA copy number were assessed through qPCR in an ABI Prism 7500 thermo cycler (Life Technologies) with the use of iQ™ SYBR Green Supermix (#170-8880 BioRad). Mitochondrial (mtND1; forward: 5’-ATGGCCAACCTCCTACTCCT-3’; reverse: 5’-GCGGTGATGTAGAGGGTGAT-3’) and nuclear (BECN1; forward: 5’-CGAGGCTCAAGTGTTTAGGC-3’; reverse: 5’-ATGTACTGGAAACGCCTTGG-3’) gene primers were used to determine relative amounts of mitochondrial to nuclear DNA . Each sample was measured in triplicate. Mitochondrial number was calculated based on the following formula: mtDNA copy number = 2ΔCt, where ΔCt = BECN1 – mtND1.
FGF-19 serum levels
For measurement of serum FGF-19 levels (pg/mL), an enzyme-linked immunosorbent assay (ELISA) kit for FGF-19 (Quantikine ELISA, R&D Systems, Minneapolis, MN) was used. All measurements were performed in duplicate according to the manufacturer’s instructions. This assay has a detection range of 31–544 pg/mL and a coefficient of variation of 4.5% for intra-assay and 5.5% inter-assay precision.
Statistical analyses were performed using the SPSS 21.0 software. Data are reported as mean ± standard deviation (SD), unless otherwise specified. Data were examined for normality according to the Shapiro–Wilks criteria. Comparisons between pre- and post-surgery time-points were performed via paired two-tailed t-tests (if parametric) and the Wilcoxon signed ranks test (if non-parametric). For categorical data, Fisher’s exact test was used. Between-group (surgery type) differences were assessed using one-way ANOVA (if parametric) and Kruskal–Wallis test (if non-parametric) using change variables, calculated as percentage change from pre-surgery values [(post/pre) × 100]. For Pearson correlation analyses, change variables [(post/pre) × 100] were log-transformed prior to analysis if non-parametric.
BPD patients exhibited greater weight loss and improvements in serum HbA1c, total and LDL cholesterol
Anthropometric and metabolic variables pre-surgery and 6 months after biliopancreatic diversion (BPD), laparoscopic greater curvature plication (LGCP) and laparoscopic adjustable gastric banding (LAGB) bariatric procedures
50.57 ± 5.88
53.24 ± 7.48
53.57 ± 11.26
30.67 ± 8.42****
17.36 ± 6.32
20.17 ± 9.36
Body weight, kg
127.7 ± 22.6
106.9 ± 18.5**
83.8 ± 3.0***
109.2 ± 16.5
97.6 ± 14.1**
89.5 ± 3.2
119.6 ± 19.1
105.3 ± 18.3**
88.1 ± 5.7
46.45 ± 7.75
39.01 ± 6.37**
84.1 ± 3.5***
40.41 ± 5.54
36.05 ± 4.62**
89.3 ± 3.4
43.95 ± 6.60
38.31 ± 7.05**
88.90 ± 4.9
0.93 ± 0.07
0.90 ± 0.07
97.7 ± 9.9
0.88 ± 0.10
0.87 ± 0.08
100.1 ± 11.1
0.90 ± 0.04
0.88 ± 0.04
98.5 ± 5.9
Body fat, %
49.59 ± 3.70
44.68 ± 4.62**
90.2 ± 6.6
48.49 ± 3.78
44.90 ± 3.71**
92.7 ± 4.6
49.54 ± 3.44
46.39 ± 4.45*
93.6 ± 5.6
8.40 ± 2.57
7.01 ± 1.73
89.1 ± 30.1
8.93 ± 2.11
7.34 ± 1.64*
84.4 ± 16.9
9.30 ± 2.65
7.07 ± 1.56**
77.4 ± 8.8
31.48 ± 21.2
17.12 ± 12.0*
71.2 ± 73.8
26.43 ± 19.4
16.76 ± 10.9*
70.6 ± 24.7
26.20 ± 6.93
15.21 ± 5.92**
61.3 ± 26.1
11.8 ± 9.74
5.3 ± 4.73*
66.1 ± 97.2
10.9 ± 9.14
5.32 ± 3.34**
61.0 ± 29.5
10.8 ± 4.13
5.07 ± 2.89**
47.1 ± 20.5
7.1 ± 0.9
5.7 ± 0.70**
72.1 ± 15.1****
7.3 ± 1.0
6.5 ± 0.9**
85.1 ± 8.5
7.0 ± 0.9
6.4 ± 0.6*
89.5 ± 12.5
53.84 ± 9.6
38.38 ± 7.8**
72.1 ± 15.1****
56.33 ± 10.5
47.93 ± 10.3**
85.1 ± 8.5
52.92 ± 10.1
46.64 ± 6.2*
89.5 ± 12.5
Total cholesterol, mmol/L
4.91 ± 1.03
3.72 ± 0.86**
75.9 ± 9.80***
4.84 ± 0.77
4.73 ± 0.82
97.8 ± 8.7
4.83 ± 0.77
4.54 ± 0.89
94.7 ± 14.9
1.43 ± 0.66
1.59 ± 0.69
117.6 ± 51.2
1.95 ± 1.39
1.38 ± 0.71
89.2 ± 33.0
1.79 ± 0.75
1.23 ± 0.50
74.0 ± 24.4
HDL cholesterol, mmol/L
1.05 ± 0.21
0.81 ± 0.22**
73.1 ± 22.0****
1.12 ± 0.33
1.15 ± 0.31
104.0 ± 15.1
1.04 ± 0.24
1.08 ± 0.25
105.0 ± 17.3
LDL cholesterol, mmol/L
3.19 ± 1.03
2.23 ± 0.67**
71.4 ± 13.2****
2.82 ± 0.69
2.94 ± 0.77
107.2 ± 25.6
2.96 ± 0.65
2.90 ± 0.82
101.6 ± 33.4
0.36 ± 0.14
0.40 ± 0.12
115.3 ± 28.6
0.42 ± 0.17
0.42 ± 0.18
102.0 ± 29.0
0.37 ± 0.11
0.38 ± 0.14
103.6 ± 25.6
BPD patients also achieved significantly greater improvements in serum HbA1c, compared with LGCP (P = 0.022) and LAGB (P = 0.002). However, after controlling for BMI, BPD and LGCP were noted to have similar effects on HbA1c reduction, whilst the difference between BPD and LAGB remained statistically significant (P = 0.028).
Post-surgery serum FGF-19 levels increased in BPD and LGCP patients, but decreased after LAGB
Comparisons of surgery-induced changes in serum FGF-19 levels between biliopancreatic diversion (BPD), laparoscopic greater curvature plication (LGCP) and laparoscopic adjustable gastric banding (LAGB) bariatric procedures
Bariatric surgery (n)
Percent of patients with increase (%)
Change from pre- to post-surgery (%)a
Surgery-induced changes in serum FGF-19 levels were significantly associated with mitochondrial number in white AT
Correlations between surgery-induced changes in serum biochemical variables and mitochondrial parameters in white adipose tissue
Of all variables captured in this study, mRNA expression of mitochondrial genes in white AT biopsies was significantly correlated only with total cholesterol and HDL cholesterol (Table 3). Indeed, post-surgery reduction in total cholesterol and HDL cholesterol levels were associated with increased expression of mitochondrial-encoded ATP synthase subunit 6 (mtATP6) and uncoupling protein 2 (UCP2), and of mtATP6 and cytochrome c oxidase subunit 4 isoform 1 (COX4I1) genes, respectively.
Control of mitochondrial gene regulation varied with bariatric surgical procedure, with greater control observed after BPD
Relationship of mitochondrial number to mitochondrial function and dynamics genes after biliopancreatic diversion (BPD), laparoscopic greater curvature plication (LGCP) and laparoscopic adjustable gastric banding (LAGB) bariatric procedures
Mitochondrial number vs.
BPD (n = 12)
LGCP (n = 15)
LAGB (n = 12)
In the present study, we hypothesized that bariatric surgery-induced elevation of serum FGF-19 target mitochondrial function in white AT and support metabolic recovery. Our findings highlight for the first time (1) a direct association between FGF-19 levels and mitochondrial number in AT consistent across three surgical procedures and (2) a differential impact of certain bariatric procedures on circulating FGF-19 levels, with (3) BPD surgery leading to a tighter control of mitochondrial gene expression than LGCP or LAGB in association with greater HbA1c, lipid and weight reduction. Thus, within the post-surgery follow-up period of our study, a step-wise order in surgical benefit based on FGF-19 levels and better metabolic health outcomes was established (BPD > LGCP > LAGB).
The finding that FGF-19 levels are inversely correlated with mitochondrial number in AT may be interpreted as a shift towards a less fragmented and more elongated mitochondrial network when FGF-19 levels are raised. This would seem of benefit, given that mitochondrial fragmentation has been associated with apoptosis [37, 38], severely compromised mitochondrial DNA integrity, inefficiency [39, 40], accumulation of reactive oxygen species , impaired oxygen consumption and ß-oxidation [7, 8], lipotoxic species accumulation , pro-inflammatory cytokine production , and impaired insulin signalling [10, 11]. Moreover, fragmentation of muscle mitochondria has been reported in several mouse and human models of obesity and type-2 diabetes [42, 43].
However, it must also be stated that long-term sustained mitochondrial elongation can compromise mitochondrial quality control and function , so mitochondrial elongation per se is not necessarily indicative of mitochondrial health, and that the cell requires a balance between both fission and fusion processes to maintain mitochondrial quality. Thus, to better understand the implications of the changes observed in mitochondrial number after surgery, we analyzed them in relation to changes in mitochondrial gene expression. Genes controlling both fusion and fission processes were tightly correlated with mitochondrial number in BPD patients, whilst in the other surgeries, the genes controlling these processes (particularly fission) appeared dysregulated. In addition, following the BPD procedure alone, mitochondrial number was significantly and positively correlated with mRNA expression of most genes assayed, covering a range of mitochondrial (biogenesis, oxidative phosphorylation, uncoupling and antioxidant) functions. This finding would support the assertion that BPD improves the control of genes involved in maintaining mitochondrial fusion/fission balance and function to a greater extent than the other two bariatric procedures in this study, and is consistent with a role of serum FGF-19 in mediating a less fragmented and potentially more functional mitochondrial network.
In contrast, in the LGCP group, the relationships between mitochondrial number and gene expression followed a significant inverse association, despite similar rise in serum FGF-19 levels compared to BPD. This seemingly paradoxical finding may be better understood within a wider context of additional factors also likely to play a role in mitochondrial recovery . Indeed, the BPD operation (unlike LGCP) produced significantly lower serum lipid levels and nearly twice as much weight loss (30% versus 17%). This is consistent with previous reports , and the notion that these two factors (weight loss and lipid recovery) may have also contributed to the enhanced mitochondrial outcomes observed after BPD versus LGCP. Further in support of this concept, total and HDL cholesterol were the only biochemical variables (apart from FGF-19) to exhibit a significant association with mitochondrial genes. Decreased cholesterol levels were directly associated with enhanced mRNA expression of complex IV (COX4I1) and V (mtATP6) genes of the electron transport chain. Similar associations were observed with the uncoupling protein 2 (UCP2) gene, which has been implicated in preventing reactive oxygen species accumulation and oxidative stress damage .
Interestingly, in the LAGB group (the only study procedure to significantly reduce serum FGF-19 levels), changes in mitochondrial gene expression in AT were (with exception of fusion genes) unrelated to mitochondrial number, suggesting a dysregulation of mitochondrial function in this cohort, potentially resulting from un-opposed fusion. Though this bariatric procedure resulted in significant weight loss and general metabolic improvement, the noted HbA1c reduction was significantly less pronounced compared with the other two procedures (even after accounting for BMI), which might be, at least in part, the result of the mitochondrial dysfunction and lower serum FGF-19 levels observed.
Previous studies in mice support the hypothesis that circulating FGF-19 targets WAT mitochondria to exert metabolic improvements. Mice challenged with a high-fat diet and treated with fexaramine (an intestine-restricted FXR agonist which potently induces intestinal FGF-15, i.e. the mouse FGF-19 homologue) exhibited significantly less weight gain, systemic inflammation and improved glucose homeostasis, with specific effects noted on visceral white AT, including reduced activation of inflammatory and lipogenic pathways, browning of white adipocytes, and increased thermogenesis . Though FGF-19 is known to exert several metabolically beneficial effects by its actions in the liver that regulate glucose and cholesterol production , recent evidence in mice further suggests that the improvement of glucose homeostasis after recombinant FGF-15 treatment is likely due to direct signaling in AT and other metabolic relevant organs rather than through the known hepatic effects . Furthermore, previous reports of positive correlations between circulating FGF-19 and adiponectin [49, 50] lend further credence to the role of FGF-19 as a regulator of WAT endocrine and metabolic function. In accordance with previous research, our findings support the hypothesis that FGF-19 targets white AT and provide evidence for the first time in humans that circulating FGF-19 levels strongly and inversely associate with mitochondrial fragmentation of this tissue.
We should note that our study has certain limitations. Firstly, though our study subjects did not follow a particular dietary regimen and led a relatively sedentary lifestyle in the period before surgery, these two factors were not controlled either before or after surgery. Secondly, despite the prospective study design, it is not possible to clarify in the context of this study the precise mechanism by which each studied surgical procedure alters serum FGF-19 levels, thus further research is required to clarify this point. However, to our knowledge, this is the first study to compare serum FGF-19 levels between these bariatric surgical procedures and to provide evidence of differential mitochondrial and metabolic outcomes based on the type of surgical procedure.
In conclusion, elevated serum FGF-19 levels post-surgery were significantly associated with improved mitochondrial health in AT, leading to greater control of mitochondrial gene regulation and overall type-2 diabetes remission. These increased FGF-19 levels were also observed to be surgery-specific, with BPD patients achieving better metabolic health outcomes compared to LGCP and LAGB (BPD > LGCP > LAGB), and highlighting mitochondria in AT as a promising potential target of FGF-19 during diabetic recovery following bariatric surgery.
- COX4I1 :
cytochrome c oxidase subunit 4 isoform 1 (Complex IV)
- DRP1 :
- FGF-19 :
fibroblast growth factor 19
- FIS1 :
mitochondrial fission 1 protein
laparoscopic adjustable gastric banding
laparoscopic greater curvature plication
- mtATP6 :
mtDNA-encoded ATP synthase subunit 6 (Complex V)
- mtND6 :
mtDNA-encoded NADH-ubiquinone oxidoreductase chain 6 (Complex II)
- OPA1 :
optic atrophy 1
- PGC1α :
peroxisome proliferator-activated receptor γ coactivator 1 α
- POLG :
mitochondrial DNA polymerase gamma
- SDHA :
succinate dehydrogenase complex II subunit A
- SOD1 :
superoxide dismutase 1
- TFAM :
mitochondrial transcription factor A
- UCP2 :
uncoupling protein 2
We would like to thank all the patients and staff associated with the study that generously gave their support to achieve the outcomes of this research.
This study was supported by the EFSD through the New Horizons Collaborative Research Initiative (EFSD New Horizons research grant) and by a National Council for Science and Technology of Mexico (CONACyT) PhD fellowship to LME (scholarship number: 313802). NIHR Clinical Lectureship supported Dr Milan K Piya. The funding bodies did not participate in the design, collection, analysis or interpretation of this study.
Availability of data and materials
The datasets collected and analysed during the current study are available from the corresponding author on reasonable request.
PGM lead the experimental design, and supported data analysis and interpretation, in addition to writing and revision of the manuscript. GT supported the experimental design for the mitochondrial work, and LME, MP and SK inputted into the design and data interpretation. LME conducted the experimental work with the tissue samples, analysed the data, and performed the writing and revision of the manuscript including preparation of the tables. IK, JV, VH, PS and MF undertook work leading to ethical approval of the project, selection and recruitment of patients, taking the clinical history, blood sample collection, serum analysis as well as input into the manuscript revision. All authors read and approved the final manuscript. PGM is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
The authors declare that they have no competing interests.
Consent for publication
Ethics approval and consent to participate
This study was approved by the Ethics Committee of the Institute of Endocrinology (Institute of Endocrinology, Ethics Committee EC: 19/5/2009, Prague, Czech Republic). All study participants provided written and informed consent in accordance with the Declaration of Helsinki.
Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
- Gibby JT, Njeru DK, Cvetko ST, Merrill RM, Bikman BT, Gibby WA. Volumetric analysis of central body fat accurately predicts incidence of diabetes and hypertension in adults. BMC Obes. 2015;2:10.View ArticlePubMedPubMed CentralGoogle Scholar
- Dennedy MC, Vidal-Puig A. An adipocentric view of the metabolic syndrome and cardiovascular disease. Curr Cardiovasc Risk Rep. 2014;8:379.View ArticleGoogle Scholar
- Kusminski CM, Scherer PE. Mitochondrial dysfunction in white adipose tissue. Trends Endocrinol Metab. 2012;23(9):435–43.View ArticlePubMedPubMed CentralGoogle Scholar
- Corkey BE, Shirihai O. Metabolic master regulators: sharing information among multiple systems. Trends Endocrinol Metab. 2012;23(12):594–601.View ArticlePubMedPubMed CentralGoogle Scholar
- Yin X, Lanza IR, Swain JM, Sarr MG, Nair KS, Jensen MD. Adipocyte mitochondrial function is reduced in human obesity independent of fat cell size. J Clin Endocrinol Metab. 2014;99(2):E209–216.View ArticlePubMedGoogle Scholar
- Liesa M, Shirihai OS. Mitochondrial dynamics in the regulation of nutrient utilization and energy expenditure. Cell Metab. 2013;17(4):491–506.View ArticlePubMedGoogle Scholar
- Choo HJ, Kim JH, Kwon OB, Lee CS, Mun JY, Han SS, Yoon YS, Yoon G, Choi KM, Ko YG. Mitochondria are impaired in the adipocytes of type 2 diabetic mice. Diabetologia. 2006;49(4):784–91.View ArticlePubMedGoogle Scholar
- Wang T, Si Y, Shirihai OS, Si H, Schultz V, Corkey RF, Hu L, Deeney JT, Guo W, Corkey BE. Respiration in adipocytes is inhibited by reactive oxygen species. Obesity. 2010;18(8):1493–502.View ArticlePubMedGoogle Scholar
- Lin Y, Berg AH, Iyengar P, Lam TK, Giacca A, Combs TP, Rajala MW, Du X, Rollman B, Li W, et al. The hyperglycemia-induced inflammatory response in adipocytes: the role of reactive oxygen species. J Biol Chem. 2005;280(6):4617–26.View ArticlePubMedGoogle Scholar
- Koves TR, Ussher JR, Noland RC, Slentz D, Mosedale M, Ilkayeva O, Bain J, Stevens R, Dyck JR, Newgard CB, et al. Mitochondrial overload and incomplete fatty acid oxidation contribute to skeletal muscle insulin resistance. Cell Metab. 2008;7(1):45–56.View ArticlePubMedGoogle Scholar
- Houstis N, Rosen ED, Lander ES. Reactive oxygen species have a causal role in multiple forms of insulin resistance. Nature. 2006;440(7086):944–8.View ArticlePubMedGoogle Scholar
- Bharadwaj MS, Tyrrell DJ, Leng I, Demons JL, Lyles MF, Carr JJ, Nicklas BJ, Molina AJ. Relationships between mitochondrial content and bioenergetics with obesity, body composition and fat distribution in healthy older adults. BMC Obes. 2015;2:40.View ArticlePubMedPubMed CentralGoogle Scholar
- Soronen J, Laurila PP, Naukkarinen J, Surakka I, Ripatti S, Jauhiainen M, Olkkonen VM, Yki-Jarvinen H. Adipose tissue gene expression analysis reveals changes in inflammatory, mitochondrial respiratory and lipid metabolic pathways in obese insulin-resistant subjects. BMC Med Genomics. 2012;5:9.View ArticlePubMedPubMed CentralGoogle Scholar
- Zhou MC, Min R, Ji JJ, Zhang S, Tong AL, Xu JP, Li ZY, Zhang HB, Li YX. Analysis of association among clinical features and shorter leukocyte telomere length in mitochondrial diabetes with m.3243A > G mitochondrial DNA mutation. BMC Med Genet. 2015;16:92.View ArticlePubMedPubMed CentralGoogle Scholar
- Scharfe C, Lu HH, Neuenburg JK, Allen EA, Li GC, Klopstock T, Cowan TM, Enns GM, Davis RW. Mapping gene associations in human mitochondria using clinical disease phenotypes. PLoS Comput Biol. 2009;5(4):e1000374.View ArticlePubMedPubMed CentralGoogle Scholar
- Loo JH, Trejaut JA, Yen JC, Chen ZS, Ng WM, Huang CY, Hsu KN, Hung KH, Hsiao Y, Wei YH, et al. Mitochondrial DNA association study of type 2 diabetes with or without ischemic stroke in Taiwan. BMC Res Notes. 2014;7:223.View ArticlePubMedPubMed CentralGoogle Scholar
- Sjostrom L. Review of the key results from the Swedish Obese Subjects (SOS) trial - a prospective controlled intervention study of bariatric surgery. J Int Med. 2013;273(3):219–34.View ArticleGoogle Scholar
- Schauer PR, Kashyap SR, Wolski K, Brethauer SA, Kirwan JP, Pothier CE, Thomas S, Abood B, Nissen SE, Bhatt DL. Bariatric surgery versus intensive medical therapy in obese patients with diabetes. N Engl J Med. 2012;366(17):1567–76.View ArticlePubMedPubMed CentralGoogle Scholar
- Warkentin LM, Majumdar SR, Johnson JA, Agborsangaya CB, Rueda-Clausen CF, Sharma AM, Klarenbach SW, Karmali S, Birch DW, Padwal RS. Weight loss required by the severely obese to achieve clinically important differences in health-related quality of life: two-year prospective cohort study. BMC Med. 2014;12:175.View ArticlePubMedPubMed CentralGoogle Scholar
- Yang J, Wang C, Cao G, Yang W, Yu S, Zhai H, Pan Y. Long-term effects of laparoscopic sleeve gastrectomy versus Roux-en-Y gastric bypass for the treatment of Chinese type 2 diabetes mellitus patients with body mass index 28-35 kg/m(2). BMC Surg. 2015;15:88.View ArticlePubMedPubMed CentralGoogle Scholar
- Vage V, Sande VA, Mellgren G, Laukeland C, Behme J, Andersen JR. Changes in obesity-related diseases and biochemical variables after laparoscopic sleeve gastrectomy: a two-year follow-up study. BMC Surg. 2014;14:8.View ArticlePubMedPubMed CentralGoogle Scholar
- Batterham RL, Cummings DE. Mechanisms of diabetes improvement following bariatric/metabolic surgery. Diabetes Care. 2016;39(6):893–901.View ArticlePubMedGoogle Scholar
- Kyrou I, Weickert MO, Gharanei S, Randeva HS, Tan BK. Fibroblast growth factors: new insights, new targets in the management of diabetes. Minerva Endocrinol. 2016. Ahead of print.
- Ryan KK, Tremaroli V, Clemmensen C, Kovatcheva-Datchary P, Myronovych A, Karns R, Wilson-Perez HE, Sandoval DA, Kohli R, Backhed F, et al. FXR is a molecular target for the effects of vertical sleeve gastrectomy. Nature. 2014;509(7499):183–8.View ArticlePubMedPubMed CentralGoogle Scholar
- Fu L, John LM, Adams SH, Yu XX, Tomlinson E, Renz M, Williams PM, Soriano R, Corpuz R, Moffat B, et al. Fibroblast growth factor 19 increases metabolic rate and reverses dietary and leptin-deficient diabetes. Endocrinology. 2004;145(6):2594–603.View ArticlePubMedGoogle Scholar
- Sachdev S, Wang Q, Billington C, Connett J, Ahmed L, Inabnet W, Chua S, Ikramuddin S, Korner J. FGF 19 and bile acids increase following Roux-en-Y gastric bypass but not after medical management in patients with type 2 diabetes. Obes Surg. 2016;26(5):957–65.View ArticlePubMedGoogle Scholar
- Pournaras DJ, Glicksman C, Vincent RP, Kuganolipava S, Alaghband-Zadeh J, Mahon D, Bekker JH, Ghatei MA, Bloom SR, Walters JR, et al. The role of bile after Roux-en-Y gastric bypass in promoting weight loss and improving glycaemic control. Endocrinology. 2012;153(8):3613–9.View ArticlePubMedPubMed CentralGoogle Scholar
- Gerhard GS, Styer AM, Wood GC, Roesch SL, Petrick AT, Gabrielsen J, Strodel WE, Still CD, Argyropoulos G. A role for fibroblast growth factor 19 and bile acids in diabetes remission after Roux-en-Y gastric bypass. Diabetes Care. 2013;36(7):1859–64.View ArticlePubMedPubMed CentralGoogle Scholar
- Jansen PL, van Werven J, Aarts E, Berends F, Janssen I, Stoker J, Schaap FG. Alterations of hormonally active fibroblast growth factors after Roux-en-Y gastric bypass surgery. Dig Dis. 2011;29(1):48–51.View ArticlePubMedGoogle Scholar
- Haluzikova D, Lacinova Z, Kavalkova P, Drapalova J, Krizova J, Bartlova M, Mraz M, Petr T, Vitek L, Kasalicky M, et al. Laparoscopic sleeve gastrectomy differentially affects serum concentrations of FGF-19 and FGF-21 in morbidly obese subjects. Obesity. 2013;21(7):1335–42.View ArticlePubMedGoogle Scholar
- Ryan KK, Kohli R, Gutierrez-Aguilar R, Gaitonde SG, Woods SC, Seeley RJ. Fibroblast growth factor-19 action in the brain reduces food intake and body weight and improves glucose tolerance in male rats. Endocrinology. 2013;154(1):9–15.View ArticlePubMedGoogle Scholar
- Morton GJ, Matsen ME, Bracy DP, Meek TH, Nguyen HT, Stefanovski D, Bergman RN, Wasserman DH, Schwartz MW. FGF19 action in the brain induces insulin-independent glucose lowering. J Clin Investig. 2013;123(11):4799–808.View ArticlePubMedPubMed CentralGoogle Scholar
- Tomlinson E, Fu L, John L, Hultgren B, Huang X, Renz M, Stephan JP, Tsai SP, Powell-Braxton L, French D, et al. Transgenic mice expressing human fibroblast growth factor-19 display increased metabolic rate and decreased adiposity. Endocrinology. 2002;143(5):1741–7.View ArticlePubMedGoogle Scholar
- Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC. Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia. 1985;28(7):412–9.View ArticlePubMedGoogle Scholar
- Friedewald WT, Levy RI, Fredrickson DS. Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clin Chem. 1972;18(6):499–502.PubMedGoogle Scholar
- Hsieh CJ, Weng SW, Liou CW, Lin TK, Chen JB, Tiao MM, Hung YT, Chen IY, Huang WT, Wang PW. Tissue-specific differences in mitochondrial DNA content in type 2 diabetes. Diabetes Res Clin Pract. 2011;92(1):106–10.View ArticlePubMedGoogle Scholar
- Frank S, Gaume B, Bergmann-Leitner ES, Leitner WW, Robert EG, Catez F, Smith CL, Youle RJ. The role of dynamin-related protein 1, a mediator of mitochondrial fission, in apoptosis. Dev Cell. 2001;1(4):515–25.View ArticlePubMedGoogle Scholar
- Lee YJ, Jeong SY, Karbowski M, Smith CL, Youle RJ. Roles of the mammalian mitochondrial fission and fusion mediators Fis1, Drp1, and Opa1 in apoptosis. Mol Biol Cell. 2004;15(11):5001–11.View ArticlePubMedPubMed CentralGoogle Scholar
- Molina AJ, Wikstrom JD, Stiles L, Las G, Mohamed H, Elorza A, Walzer G, Twig G, Katz S, Corkey BE, et al. Mitochondrial networking protects beta-cells from nutrient-induced apoptosis. Diabetes. 2009;58(10):2303–15.View ArticlePubMedPubMed CentralGoogle Scholar
- Las G, Serada SB, Wikstrom JD, Twig G, Shirihai OS. Fatty acids suppress autophagic turnover in beta-cells. J Biol Chem. 2011;286(49):42534–44.View ArticlePubMedPubMed CentralGoogle Scholar
- Brookheart RT, Michel CI, Schaffer JE. As a matter of fat. Cell Metab. 2009;10(1):9–12.View ArticlePubMedPubMed CentralGoogle Scholar
- Kelley DE, He J, Menshikova EV, Ritov VB. Dysfunction of mitochondria in human skeletal muscle in type 2 diabetes. Diabetes. 2002;51(10):2944–50.View ArticlePubMedGoogle Scholar
- Bach D, Pich S, Soriano FX, Vega N, Baumgartner B, Oriola J, Daugaard JR, Lloberas J, Camps M, Zierath JR, et al. Mitofusin-2 determines mitochondrial network architecture and mitochondrial metabolism. A novel regulatory mechanism altered in obesity. J Biol Chem. 2003;278(19):17190–7.View ArticlePubMedGoogle Scholar
- Twig G, Elorza A, Molina AJ, Mohamed H, Wikstrom JD, Walzer G, Stiles L, Haigh SE, Katz S, Las G, et al. Fission and selective fusion govern mitochondrial segregation and elimination by autophagy. EMBO J. 2008;27(2):433–46.View ArticlePubMedPubMed CentralGoogle Scholar
- Vila M, Ruiz O, Belmonte M, Riesco M, Barcelo A, Perez G, Moreiro J, Salinas R. Changes in lipid profile and insulin resistance in obese patients after Scopinaro biliopancreatic diversion. Obes Surg. 2009;19(3):299–306.View ArticlePubMedGoogle Scholar
- Arsenijevic D, Onuma H, Pecqueur C, Raimbault S, Manning BS, Miroux B, Couplan E, Alves-Guerra MC, Goubern M, Surwit R, et al. Disruption of the uncoupling protein-2 gene in mice reveals a role in immunity and reactive oxygen species production. Nat Genet. 2000;26(4):435–9.View ArticlePubMedGoogle Scholar
- Fang S, Suh JM, Reilly SM, Yu E, Osborn O, Lackey D, Yoshihara E, Perino A, Jacinto S, Lukasheva Y, et al. Intestinal FXR agonism promotes adipose tissue browning and reduces obesity and insulin resistance. Nat Med. 2015;21(2):159–65.View ArticlePubMedPubMed CentralGoogle Scholar
- Wu X, Ge H, Lemon B, Weiszmann J, Gupte J, Hawkins N, Li X, Tang J, Lindberg R, Li Y. Selective activation of FGFR4 by an FGF19 variant does not improve glucose metabolism in ob/ob mice. Proc Natl Acad Sci U S A. 2009;106(34):14379–84.View ArticlePubMedPubMed CentralGoogle Scholar
- Reiche M, Bachmann A, Lossner U, Bluher M, Stumvoll M, Fasshauer M. Fibroblast growth factor 19 serum levels: relation to renal function and metabolic parameters. Horm Metab Res. 2010;42(3):178–81.View ArticlePubMedGoogle Scholar
- Mraz M, Lacinova Z, Kavalkova P, Haluzikova D, Trachta P, Drapalova J, Hanusova V, Haluzik M. Serum concentrations of fibroblast growth factor 19 in patients with obesity and type 2 diabetes mellitus: the influence of acute hyperinsulinemia, very-low calorie diet and PPAR-alpha agonist treatment. Physiol Res. 2011;60(4):627–36.PubMedGoogle Scholar