Bariatric surgery emphasizes biological sex differences in rodent hepatic lipid handling
© The Author(s). 2017
Received: 28 September 2016
Accepted: 18 January 2017
Published: 28 January 2017
Eighty percent of patients who receive bariatric surgery are women, yet the majority of preclinical studies are in male rodents. Because sex differences drive hepatic gene expression and overall lipid metabolism, we sought to determine whether sex differences were also apparent in these endpoints in response to bariatric surgery.
Two cohorts of age-matched virgin male and female Long-Evans rats were placed on a high fat diet for 3 weeks and then received either Sham or vertical sleeve gastrectomy (VSG), a surgery which resects 80% of the stomach with no intestinal rearrangement.
Each sex exhibited significantly decreased body weight due to a reduction in fat mass relative to Sham controls (p < 0.05). Microarray and follow-up qPCR on liver revealed striking sex differences in gene expression after VSG that reflected a down-regulation of hepatic lipid metabolism and an up-regulation of hepatic inflammatory pathways in females vs. males after VSG. While the males had a significant reduction in hepatic lipids after VSG, there was no reduction in females. Ad lib-fed and fasting circulating triglycerides, and postprandial chylomicron production were significantly lower in VSG relative to Sham animals of both sexes (p < 0.01). However, hepatic VLDL production, highest in sham-operated females, was significantly reduced by VSG in females but not males.
Taken together, although both males and females lose weight and improve plasma lipids, there are large-scale sex differences in hepatic gene expression and consequently hepatic lipid metabolism after VSG.
KeywordsVertical sleeve gastrectomy Triglycerides Liver Bariatric surgery Sex difference
To date, bariatric surgical procedures are the most successful method to treat obesity and resolve metabolic comorbidities. Vertical sleeve gastrectomy (VSG) is a particular type of bariatric surgery which removes about 80% of the stomach along the greater curvature and involves no intestinal rearrangement. VSG is rapidly expanding in utilization due to the fact that it is highly efficacious at causing weight loss (60–65%) [1, 2] and improving type 2 diabetes and hyperlipidemia .
The mechanism(s) that underlie the efficacy of bariatric surgery are unknown but our contention is that there are key molecular events triggered by surgery that have lasting effects on metabolic homeostasis. Many groups, including our own, are focused on utilizing rodent models of bariatric surgery in order to identify these molecular events [4–7]. However, despite the fact that women represent approximately 80% of the bariatric surgery patient population, the vast majority of the preclinical work, has been in male rodents (see [8–10] as exceptions). Overall, this distinction may not seem important; surgery is highly efficacious regardless of sex. However, biological sex has potent effects on lipid metabolism that extends beyond region-specific fat distribution. For example, in response to metabolic stress, such as weight loss or exercise, fat is mobilized more readily in women [11–14]. This is also evident from an evolutionary perspective where transcriptional profiling of hepatic genes revealed that 70% of 1249 genes were upregulated in females and many of those genes were related to lipid metabolism . Thus, if we are to understand the molecular changes underlying the success of surgery, we cannot ignore the potential influence of sex on the affected pathways.
Our previous data have demonstrated a reduction in circulating  and hepatic  triglycerides in male rats following VSG. In contrast, female rats that had VSG prior to pregnancy but were sacrificed several months after pregnancy and lactation, demonstrated elevated hepatic triglycerides . It remains unknown whether this would also be seen in female rats that had never been pregnant. Thus, the purpose of the present study was to directly compare hepatic lipid metabolism in virgin male and female rats after VSG.
All procedures for animal use were approved by the University of Cincinnati Institutional Animal Care and Use Committee and follow the guidelines outlined in the National Institutes of Health guide for the care and use of laboratory animals (NIH Publications No. 8023, revised 1978). Two cohorts of age-matched (8 weeks) Long Evans rats (male body weight 225–250 g, female body weight 175–200 g) (Harlan Laboratories, Indianapolis, IN) were individually housed and maintained on a 12/12-h light/dark cycle at 25 °C and 50–60% humidity. We chose to match the animals by age because of the complications involved in matching by body mass requiring either that the males be severely food restricted or the females much older than the males. Further, complicating matching by body mass, male and female rats have different weight gain trajectories in response to high-fat diet.
Following acclimatization to the facilities, animals were given ad libitum access to water and a custom-made palatable high-fat diet (high-fat diet) that we have used previously  (D12451, Research Diets, New Brunswick, NJ, 4.73 kcal/g, 45% butter fat; 19g of butter oil and 1 g of soybean oil to provide essential fatty acids) for 3 weeks prior to surgery and maintained on the diet until the studies were terminated. Animals were assigned to receive either Sham or VSG surgery in a counterbalanced fashion by body weight. Cohort 1 (male, n = 6; female, n = 6 rats) was studied for hepatic microarray gene expression after surgery while cohort 2 (male, n = 20 and female, n = 20 rats) was studied for the phenotypic response to surgery.
Four days prior to surgery, body composition was assessed using an EchoMRI analyzer (Houston, TX). Animals were fed Osmolite OneCal liquid diet but no solid-food for 48-h prior to surgery. VSG was performed as previously described . Briefly, it consisted of a midline abdominal laparotomy with exteriorization of the stomach. The lateral 80% of the stomach was excised using an ETS 35-mm staple gun (Ethicon Endo-Surgery, Cincinnati, OH), leaving a tubular gastric remnant in continuity with the esophagus. This gastric sleeve was then reintegrated into the abdominal cavity and the abdominal wall was closed in layers. For the sham surgery, an abdominal laparotomy was performed, light manual pressure was applied with to the exteriorized stomach, and then the abdomen was closed in layers.
For 3 days following surgery, all rats received twice-daily subcutaneous injections of 5 mL saline and 0.20 mL Buprenex® (0.05mg/kg), and animals were maintained on Osmolite liquid diet which was replaced with high fat diet on day 4.
During post-operative week 9, animals were fasted for 24 h and then received either 2 mL (males) or 1.3 mL (females) of olive oil. Blood was taken again at 2-h post-gavage and then animals were killed by an injection of Fatal Plus (1 mg/g body weight) and tissues were collected to determine the impact of sex and surgery on liver triglycerides and hepatic gene expression. The time point was chosen based on previously published work that demonstrates it reflects the time point of the initial rise in both plasma and hepatic uptake of olive oil . Olive oil was used as this is the type of fat we used in previous studies . Liver tissue was collected freshly frozen in methyl butane and then stored in −80 °C until further processing. Hepatic RNA was extracted using a QIAGEN miniprep RNA kit (QIAGEN, Inc, Valencia, CA). The microarrays were performed by the CCHMC Genomics Core. The quality of the total RNA was checked by a 2100 Agilent Bioanalyzer using the RNA 6000 Nano Assay. The GeneChip 3’ IVT Express Kit (Affymetrix) was used to make double-stranded cDNA from 0.3 μg of total RNA. An in vitro transcription reaction creates biotin-labeled cRNA target. The cRNA target is chemically fragmented and then hybridized to an Affymetrix Genechip Array. Then, 15 μg of fragmented cRNA was then hybridized to a Rat Genome 230 2.0 Array (Affymetrix). Probe arrays were incubated at 45 °C for 16 h in the hybridization oven 640 (Affymetrix) rotating at 60 rpm. Probe arrays were washed and stained using the Fluidics Station 450 (Affymetrix) utilizing the fluidics protocol FS450-0001. The stain and Antibody solutions are produced by Affymetrix and contained in the Genechip Hybridization Wash and Stain Kit. GeneChips were scanned using the Affymetrix GeneChip Scanner 3000 7G. The .cel and .chp files for the samples were created using the Expression Console software (Affymetrix).
Relative hepatic gene expression from male and female (Sham and VSG treatments) rats was obtained using the Affymetrix Gene Chip Rat 230 2.0. Data was normalized using the RMA algorithm to the median of the control samples (sex-specific Sham). We further filtered the data, requiring a signal intensity of 75 in at least one of the four experimental conditions. In order to generate gene-sets of differentially regulated significant and relevant genes, we formed pairwise comparisons between select conditions with a fold-change cut-off of 1.5 and accepted significance at p < 0.05. Additionally, we performed a ranking procedure to select the 500 top- and bottom-expressed genes for each condition. All expression analysis was performed in GeneSpring 12.5. Gene sets were submitted to ToppGene for ontological analysis, which uses unbiased methods to determine gene set enrichment for pathways, biological processes, and molecular functions.
Body weight, composition, and food intake
In a second cohort of VSG and sham animals, food intake and body weights were measured daily for the first week following surgery. Body composition (fat and lean mass) was determined as described above before high fat diet (3 weeks prior to surgery), 4 d prior to surgery, and then 4 and 16 weeks following surgery. During the postoperative period, several physiological studies were performed to determine the impact of biological sex on physiological responses to bariatric surgery, in particular, aspects of lipid metabolism were evaluated.
Glucose tolerance and baseline measurements
During postoperative week 5, animals were fasted for ~6 h following the onset of the light. Baseline blood glucose was measured using an AccuChek glucometer. Rats were administered 50% dextrose by oral gavage at a flat dose equivalent to 1.5 g of glucose per the average body mass of the respective sex. Thus, all males received 1.5mL and all females received 0.9mL of 50% dextrose. Blood glucose was then measured at 15, 30, 45, 60, and 120 min following dextrose administration. In addition, plasma from the 0 time point was also used to determine fasting levels of circulating triglyceride and cholesterol.
Physiologic disappearance of triglycerides
During post-operative week 6, animals were allowed ad libitum access to high fat diet for 24 h prior the experiment. Hoppers were then removed at lights on and tail vein blood sample taken at time 0, 4, 8, and 24 h following hopper removal to assess plasma triglycerides.
Lipid absorption through fecal analysis
During post-operative week 8, 24 h fasted rats received a gavage of a lipid emulsion containing 20% soybean oil, 1.2% egg phospholipid, 2.5% glycerin, 2.5% sucrose polybehenate at a volume of 5 mL/kg. Fecal samples were collected 24 and 48 h later. Fecal lipid content was assayed by gas chromatography of fatty acid methyl esters by the UC Mouse Metabolic Phenotyping Core (MMPC). Dietary lipid absorption was estimated using a ratio of total fecal fatty acids to sucrose polybehenate.
Post-prandial lipid distribution
During post-operative week 23, animals were fasted for 24h, baseline blood was sampled for subsequent analysis of plasma triglyceride, and then the animals each received a gavage of radioloabeled [9, 10(N)-3H] glycerol trioleate (100 μCi; #NET431L005MC, Perkin Elmer) mixed with 5.0 mL/kg of olive oil. Blood was taken again 2h after the gavage and then animals were sacrificed in a counter-balanced fashion (by sex) by an injection of Fatal Plus (1 mg/g body weight). Tissues were collected to determine the impact of sex and surgery on postprandial lipid distribution, liver triglycerides, and gene expression.
Postprandial chylomicron production
During post-operative week 7, animals were fasted for 24 h and then within 1 h of lights received an intraperitoneal injection of 1 g/kg poloxamer 407 (P-407; Sigma-Aldrich, St Louis, MO), a lipoprotein lipase inhibitor. Then 15 min later, a baseline blood sample from the tail vein was collected (t = 0) and an intragastric gavage of 0.5 mL/kg olive oil was delivered (average dose: males 240μl and females 130μl olive oil). Tail vein blood was then collected at 2 and 6 h following gavage.
Hepatic VLDL production
During the 18th postoperative week, rats were fasted for 24 h, baseline blood samples were collected, and then rats received an intraperitoneal injection of 1 g/kg poloxamer 407 (P-407; Sigma-Aldrich, St Louis, MO). Blood was sampled again at 2, 4, and 6 h after injection.
RNA processing and real-time PCR
Real-time QPCR validation of genes using hepatic samples in cohort 1
Statistics (two-way ANOVA)
100 ± 7a
75 ± 5b
91 ± 3
94 ± 7
p (surgery × sex) < 0.05
100 ± 10a
49 ± 6b
2 ± 1c
4 ± 1c
p (surgery × sex) < 0.001
100 ± 9
72 ± 11
90 ± 6
79 ± 12
100 ± 6a
73 ± 6b
54 ± 4b
53.1 ± 4b
p (surgery × sex) < 0.05
100 ± 12
70 ± 11
17 ± 5
14 ± 2
p (sex) < 0.001
100 ± 8a
64 ± 5c
29 ± 3b
31 ± 3b
p (surgery × sex) < 0.01;
100 ± 4
82 ± 6
68 ± 5
67 ± 6
p (sex) < 0.001
100 ± 12
104 ± 12
35 ± 3
68 ± 7
p (sex) < 0.001
100 ± 9
59 ± 8
106 ± 10
102 ± 11
p (sex) < 0.05, p (surgery) < 0.05,
100 ± 13
67 ± 10
85 ± 13
75 ± 11
p(surgery) < 0.05
100 ± 6
68 ± 7
70 ± 10
58 ± 5
p (surgery) < 0.05, p (sex) < 0.01
100 ± 11a
66 ± 7b
20 ± 1c
21 ± 3c
p (surgery × sex) < 0.05;
100 ± 24
85 ± 11
40 ± 7
44 ± 15
p (sex) < 0.001
100 ± 7a
64 ± 5b
35 ± 2c
37 ± 3c
p (surgery × sex) < 0.001
100 ± 15a
57 ± 5b
91 ± 7a
92 ± 6a
p (surgery × sex) < 0.001
100 ± 6a
75 ± 5b
81 ± 4b
76 ± 5b
p (surgery × sex) < 0.05
100 ± 10
106 ± 6
88 ± 5
116 ± 8
p (surgery) < 0.05
100 ± 7a
59 ± 8b
74 ± 6b
64 ± 5b
p (surgery × sex) < 0.05
100 ± 4
80 ± 4
106 ± 6
93 ± 7
P(surgery) < 0.01
100 ± 8
92 ± 12
158 ± 13
185 ± 16
P(sex) < 0.001
Tissue and Plasma Analytes
Liver triglycerides were measured using an enzymatic assay (#T7532-120, Pointe Scientific, Canton MI). Plasma was stored at -80 °C until further processing. Plasma was diluted 1:20 in saline in order to measure triglycerides (#TR22421, Infinity Triglyceride Reagent, Thermo Scientific, Waltham, MA). Cholesterol (Infinity Cholesterol, #TR13421, Thermo Scientific, Waltham, MS), total bile acids (#BQ 092A-EALD, BQkits Diagnostics, San Diego, CA), β-hydroxybutyrate (#SBHR-100, Fisher Scientific, Waltham, MA), and non-esterified fatty acids (Wako Diagnostics, Richmond, VA) were measured using enzymatic assays. TGFβ measurements were made using a standard ELISA (#MB100B, R&D Systems, Minneapolis, MN). Estradiol and progesterone assays were performed by the Vanderbilt Hormone Assay and Analytical Services Core (Vanderbilt University, Nashville, TN).
Except for the microarray data which was analyzed as described above, all statistical analyses were performed using GraphPad Prism version 4.0 (GraphPad Software, San Diego, California, USA). To observe time-wise differences, two-way ANOVA (variables: surgery/sex and time) with a Bonferroni post hoc test was used. When time was not a variable, a two-way ANOVA for sex and surgery with a Bonferroni post hoc test was used. All results are given as means ± SEM. Results were considered statistically significant when p < 0.05.
We then performed qPCR on liver tissue in order to validate the striking microarray findings. Similar to the array and consistent with our in vivo findings, genes that regulate or are involved in cholesterol synthesis and VLDL production (MTTP, DGAT2, ACAT2, CD36, LDLR, LRH1) and lipid metabolism (ACOX1, SREBP, ERα) were down-regulated by VSG in females (Table 1).
Plasma metabolite measurements *p < 0.05, **p < 0.01, ***p < 0.001. Data are presented as mean ± SEM
2-Way ANOVA Statistics
339 ± 44
107 ± 21
439 ± 55
153 ± 27
p (surgery) < 0.05
91 ± 4
87 ± 3
71 ± 4
62 ± 5
p (sex) < 0.001
1.5 ± 0.1
1.5 ± 0.1
1.9 ± 0.1
1.7 ± 0.2
1.8 ± 0.1
1.6 ± 0.1
2.3 ± 0.1
1.9 ± 0.1
p (sex) < 0.001; p (surgery) < 0.01
Total bile acids (μM/L)
23 ± 3
93 ± 19
13 ± 5
45 ± 9
p (sex) < 0.001; p (surgery) < 0.05
Fat absorption (%)
93 ± 2
82 ± 5
90 ± 4
82 ± 3
p (surgery) < 0.01
70 ± 11
39 ± 4
28 ± 2
20 ± 3
p (sex) < 0.001; p (surgery) < 0.01
6.4 ± 1.5
4.9 ± 0.6
We then examined whether postprandial lipids were preferentially trafficked to the liver in VSG females compared to males. Basal levels of plasma triglycerides were greatest in sham surgery males compared to all other groups (Fig. 4c; p < 0.01) and following the gavage of a radiolabeled lipid emulsion lead to there were similar increases in plasma triglycerides (Fig. 4c) in the in males and females regardless of surgery. In the liver, and independent of surgery, females had significantly greater 3H uptake than males (main effect of sex, p < 0.001; Fig. 4e). However, surgery did not alter the amount of 3H-glycerol trioleate uptake into the liver, gastrocnemius, or gonadal fat (epididymal for male and peri-ovarian for females) tissues but did cause a significant increase of 3H-glycerol trioleate in subcutaneous fat of VSG compared to Sham males (p < 0.05) (Fig. 4e).
We next determined whether hepatic VLDL production, which is the predominant source of triglycerides under fasting conditions, was altered by biological sex. To do this, we administered poloxamer 407 to 16h fasted animals. Sham females had significantly greater VLDL production compared to all other groups and importantly, VSG lowered this to the level of males at 4 and 6 h (Fig. 5c). Likewise, the rate of triglyceride appearance over time (slope of the data in Fig. 5d) was significantly reduced by VSG in females but not males (sex × surgery interaction, p < 0.001). These data suggest that hepatic triglyceride export is slowed by VSG in females.
Men and women have distinct regulation of lipid metabolism. These differences go beyond region-specific fat distribution. For example, at the same level of obesity, women have a lower risk for type 2 diabetes mellitus (T2DM) and cardiovascular disease , in response to metabolic stress, such as weight loss or exercise, fat is mobilized more readily in women [11–14], and lastly genome-wide association studies have identified multiple sex-dependent loci in medically-relevant traits . Here, we find that bariatric surgery emphasizes sex differences specifically in hepatic lipid handling such that genes that regulate lipid metabolism are down-regulated by VSG resulting in lower VLDL export and maintenance of sham-level hepatic triglycerides. This is in contrast to the surgery-induced reduction in hepatic triglycerides by VSG in males which is not explained by changes in lipid uptake or export and likely is reflected by intrahepatic changes in metabolism .
Similar to clinical reports, VSG was a successful strategy in causing weight loss and improving plasma glucose and lipid levels in both male and female rats [24–26]. It is only to this extent of physiology that most clinical studies have probed and they report similar responses to surgery between men and women. While some studies have observed similar clinical responses to bariatric surgery between men and women , exploration of the bariatric outcomes longitudinal database (BOLD) did find that sex contributed to the variability of surgical outcome . However, a true physiological comparison of the responses to surgery in men vs. women is limited by the small number of male patients in addition to the need for the appropriate resources for these studies. For example, hormone status likely influences the surgical outcome; however, the large- and even small-scale studies that included sex as a variable in models to evaluate surgical success were unable to actually measure hormone status [9, 28].
Both clinical and preclinical data clearly reflect sexual dimorphisms in lipoprotein profiles and indicate that females rely more on lipid flux during times of metabolic stress [13, 14, 29]. Importantly, our rodent model results present here also have parallels to clinical work. As we observed with our rats, women have greater VLDL production than men  and this has been found to be due specifically to greater levels of estradiol in women . Lastly, in a group of eight women and one man, VLDL production was found to be reduced by RYGB . Whether this would influence hepatic triglyceride stores in patients remains to be determined. Retrospective studies suggest an improvement in hepatic lipids after RYGB [31–34]. However, a few studies report either a lack of improvement or even increased steatosis after RYGB [35, 36]. The bottom line is that even though there is an average improvement of liver fat, this does not happen in all of patients after RYGB suggesting that there is individual variation in response to the surgery. In addition, postoperative timing of hepatic lipid measures , type of surgery  and technique used to assess hepatic lipids could all influence conclusions about the impact of surgery on hepatic lipids.
The present data support previous findings that hepatic lipid flux is quite different in males and females; differences which typically protect the female from hepatic lipid accumulation. However, VSG changes this metabolic profile preventing further reductions in hepatic triglycerides in female rodents. It is possible that the lack of an effect of VSG on hepatic triglycerides in females is due to a floor effect; i.e., the Sham-operated females already had lower hepatic triglyceride levels compared to males. Our previous research demonstrated that high fat vs. chow-fed female rats have increased hepatic triglycerides . Thus, in our current study we should have enough of an experimental signal to detect a surgery-induced reduction in hepatic triglycerides if one existed. It is important to note that this level of hepatic triglycerides is still lower than Sham males, and explains why glucose tolerance was lower in Sham and VSG females vs. Sham males. Interestingly, our previous research has shown that VSG prior to pregnancy leads to a long-term increase in hepatic triglycerides but these animals maintained a surgery-induced improvement in glucose tolerance . Women, and female zucker diabetic fatty rats, ob/ob and db/db mice all display protection from diabetes or hyperglycemia, respectively compared to men/males [22, 38–41]. While we hypothesize that VSG is yet another model whereby females are able to protect hepatic glucose metabolism in the face of higher liver triglycerides, we also admit that the short length of time on HFD, as well as the fact that the animals are maintained on HFD post-operatively, may limit the translation of this work to humans with longer-standing obesity and post-operative changes in feeding behavior that are metabolically favorable.
An interaction between reproductive hormones and surgery likely drives changes in lipid metabolism in females. Estradiol has been demonstrated to be a primary mechanism driving sex differences in lipid metabolism [13, 42]. In an elegant series of studies, Zhu et al.  found that hepatic estrogen receptor alpha (ER α) signaling plays a crucial role in regulating lipid flux across the liver. Namely, hepatic ER α signaling limited liver fat synthesis but maintained triglyceride export in the setting of hyperinsulinemia with the net result of reduced hepatic triglycerides. Thus, our finding that hepatic triglycerides failed to reduce after VSG may be explained by the reduced hepatic ERα expression (Table 1) also observed in the females after VSG. Interestingly, reduced hepatic ER α has been found in patients with non-alcoholic steatohepatitis  demonstrating clinical relevance of hepatic estrogen signaling.
In conclusion, our results indicate that male and female rodents have similar qualitative responses to VSG. However, there are large-scale changes in the genes regulating lipid metabolism in female but not male rodents in response to VSG. In addition, VSG causes less export of triglycerides in a fasting state in females while lipid uptake and export are not changed by VSG in males. As a result, while males have a significant reduction females retain high-fat levels hepatic triglycerides. In our efforts to understand the molecular underpinnings of bariatric surgery, research has mostly neglected the contribution of sex to outcomes. The current results demonstrate that studying female rodents is necessary to advance our understanding of the molecular mechanisms of bariatric surgery for the greater than 80% of bariatric surgery patients that are female.
Non-esterified fatty acids
Quantitative polymerase chain reaction
Roux-en-Y gastric bypass
Type 2 diabetes mellitus
Very low density lipoprotein
Vertical sleeve gastrectomy
The authors thank Jose Berger, Alfor Lewis, Ken Parks, Kathi Smith and Mouhamadoul Toure for their surgical expertise and Nicholas Bedel for assistance with animal work. Microarrays were run with the assistance of Shawn Smith, Cincinnati Children’s Hospital Medical Center. We are grateful for assay work by Sarah Huesman (MMPC) and Radha Krishna (MDI Assay Core) and Joshua Pressler (UC).
The work of the laboratory is supported in part by NIH Awards, DK082480 (DAS), DK093848 (RJS), F32HD68103 (BEG) and the MMPC is supported via grant DK059630. The laboratory also has potential financial competing interests as we receive research funding from Ethicon Endo-Surgery Inc. (RJS and DAS), F. Hoffman-La Roche Ltd. (RJS), Pfizer Inc (RJS), and Novo Nordisk A/S (RJS and DAS).
Availability of data and materials
The datasets during and/or analyzed during the current study available from the corresponding author on reasonable request.
BEG, RGA, JES, MRA, and EKM were responsible for executing experiments. RK was responsible for Microarray Analysis. BEG, MRA, PH, RJS, and DAS were responsible for planning experiments. BEG, DAS, PH, and RJS were responsible for interpretation of data and literature, drafting of the manuscript, and approval of the final version for publication.
The laboratory also has potential financial competing interests as we receive research funding from Ethicon Endo-Surgery Inc. (RJS and DAS), F. Hoffman-La Roche Ltd. (RJS), Pfizer Inc (RJS), and Novo Nordisk A/S (RJS & DAS).
Consent for publication
All procedures for animal use were approved by the University of Cincinnati Institutional Animal Care and Use Committee and follow the guidelines outlined in the National Institutes of Health guide for the care and use of laboratory animals (NIH Publications No. 8023, revised 1978).
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.
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