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. 2020 May 1;318(5):E678-E688.
doi: 10.1152/ajpendo.00441.2019. Epub 2020 Feb 18.

Sleeve gastrectomy enhances glucose utilization and remodels adipose tissue independent of weight loss

David A Harris  1 , Amir Mina  2 , Dimitrije Cabarkapa  2 , Keyvan Heshmati  1 , Renuka Subramaniam  1 , Alexander S Banks  2 , Ali Tavakkoli  1 , Eric G Sheu  1
Affiliations

Sleeve gastrectomy enhances glucose utilization and remodels adipose tissue independent of weight loss

David A Harris et al. Am J Physiol Endocrinol Metab. .

Abstract

Sleeve gastrectomy (SG) induces weight loss-independent improvements in glucose homeostasis by unknown mechanisms. We sought to identify the metabolic adaptations responsible for these improvements. Nonobese C57BL/6J mice on standard chow underwent SG or sham surgery. Functional testing and indirect calorimetry were used to capture metabolic phenotypes. Tissue-specific glucose uptake was assessed by 18-fluorodeoxyglucose (18-FDG) PET/computed tomography, and RNA sequencing was used for gene-expression analysis. In this model, SG induced durable improvements in glucose tolerance in the absence of changes in weight, body composition, or food intake. Indirect calorimetry revealed that SG increased the average respiratory exchange ratio toward 1.0, indicating a weight-independent, systemic shift to carbohydrate utilization. Following SG, orally administered 18-FDG preferentially localized to white adipose depots, showing tissue-specific increases in glucose utilization induced by surgery. Transcriptional analysis with RNA sequencing demonstrated that increased glucose uptake in the visceral adipose tissue was associated with upregulation in transcriptional pathways involved in energy metabolism, adipocyte maturation, and adaptive and innate immune cell chemotaxis and differentiation. SG induces a rapid, weight loss-independent shift toward glucose utilization and transcriptional remodeling of metabolic and immune pathways in visceral adipose tissue. Continued study of this early post-SG physiology may lead to a better understanding of the anti-diabetic mechanisms of bariatric surgery.

Keywords: diabetes; glucose utilization; immunometabolism; respiratory exchange ratio; sleeve gastrectomy.

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Conflict of interest statement

The content is solely the responsibility of the authors and does not necessarily represent the official views of Harvard Catalyst, Harvard University and its affiliated academic healthcare centers, or the National Institutes of Health. No conflicts of interest, financial or otherwise, are declared by the authors.

Figures

Fig. 1.
Fig. 1.
Experimental design. 18-FDG, 18-fluorodeoxyglucose; CLAMS, comprehensive lab animal-monitoring systems; GLP1, glucagon-like peptide 1; ITT, insulin tolerance testing; OGTT, oral glucose tolerance testing; POD, postoperative day; RNA-seq, RNA sequencing; SG, sleeve gastrectomy; VAT, visceral adipose tissue.
Fig. 2.
Fig. 2.
Postoperative weight (A), daily food intake (B), and body composition (C) between sham (n = 4) and sleeve gastrectomy (SG; n = 4) mice. A and B: n = 4.4; C: n = 5.5, and data are representative of 3 biologic replicates. Comparisons by Student’s t tests. *P < 0.05. ns, not significant.
Fig. 3.
Fig. 3.
A and B: oral glucose tolerance testing at 2 and 4 wk, respectively [A: sleeve gastrectomy (SG) n = 9, sham n = 10; B: n = 4.4]. C: insulin tolerance testing at 2 wk (SG n = 6, sham n = 6). D: total glucagon-like peptide 1 (GLP1) levels at 15 min following glucose challenge (SG n = 4, sham n = 5). Comparisons made using t tests. *P < 0.05, ***P < 0.001. ++One sham and 2 SG animals had to be rescued from hypoglycemia at this time point. ns, not significant.
Fig. 4.
Fig. 4.
Sleeve gastrectomy (SG) mice have continuously elevated respiratory exchange ratios (RERs; average 0.9–1.05), indicating preferential glucose utilization during both light and dark cycles. A: sham mice demonstrate normal RER excursions, reflective of mixed lipid/glucose utilization. SG mice have higher average RER (B) and lower energy expenditure (EE; C) over a 24-h period during the dark cycle and during the light cycle. Combination of 3 biologic replicates. SG n = 15, sham n = 14; t test. *P < 0.05, **P < 0.01, ***P < 0.001.
Fig. 5.
Fig. 5.
A: representative PET/computed tomography images from sham (left) and sleeve gastrectomy (SG; right) animals, 1 h after oral 18-fluorodeoxyglucose (18-FDG) administration during postoperative wk 2. Red denotes high and green low 18-FDG avidity. B: time activity curves were generated (n = 2.2). C: 18-FDG avidity across all fat depots, as measured by well counter (C: SG n = 4, sham n = 5). *P < 0.05. SUV, standardized uptake value.
Fig. 6.
Fig. 6.
ChEA2016 transcription pathway analysis showing the most upregulated (left) and downregulated (right) transcription pathways. Data are organized as clustergrams with a red bar denoting a gene contributing to the pathway expression. Only pathways with an adjusted P < 0.05 are included. Pathway titles are followed by the combined score. Base > 50, log change > 0.5, adjusted P < 0.05. E2A, E2A immunoglobulin enhancer-binding factor E12/E47; FOXO1, forkhead box protein O1; GATA3, gata-binding protein 3; IRF8, IFN regulatory factor 8; MECOM, myelodysplastic syndrome 1 and ecotropic viral integration site 1 complex locus; MTF2, metal response element-binding transcription factor 2; NCOR, nuclear receptor corepressor; PPARG, proliferator-activated receptor γ; SMRT, silencing mediator of retinoid and thyroid hormone receptors; SUZ12, polycomb-repressive complex 2 subunit.
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