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

Harris, David A.; Mina, Amir I.; Čabarkapa, Dimitrije; Heshmati, Keyvan; Subramaniam, Renuka; Banks, Alexander S.; Tavakkoli, Ali; Sheu, Eric G.

doi:10.1101/779033

Cited by 3 publications

(3 citation statements)

References 72 publications

(90 reference statements)

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“…Despite a significant reduction in tumor burden compared to obese HFD-Sham mice, VSG-treated mice demonstrated upregulated mammary fat pad inflammation to levels greater than those of obese mice. Our finding of elevated inflammation in the mammary fat pad after VSG is consistent with several studies reporting inflammation in adipose depots following bariatric surgery in murine models [34-37, 53]. The persistent inflammation identified after bariatric surgery in adipose tissue could be due to adipose remodeling following rapid weight loss, or wound repair signaling from the surgical injury itself.…”

Section: Discussionsupporting

confidence: 91%

Response to immune checkpoint blockade improved in pre-clinical model of breast cancer after bariatric surgery

Sipe

Chaib

Korba

et al. 2022

Preprint

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Bariatric surgery is becoming more prevalent as a sustainable weight loss approach, with vertical sleeve gastrectomy (VSG) being the first line of surgical intervention. We and others have shown that obesity exacerbates tumor growth while diet-induced weight loss impairs obesity-driven progression. It remains unknown how bariatric surgery-induced weight loss impacts cancer progression or alters responses to therapy. Using a pre-clinical model of diet induced obesity followed by VSG or diet-induced weight loss, breast cancer progression and immune checkpoint blockade therapy was investigated. Weight loss by bariatric surgery or weight matched dietary intervention before tumor engraftment protected against obesity-exacerbated tumor progression. However, VSG was not as effective as dietary intervention in reducing tumor burden despite achieving similar extent of weight and adiposity loss. Circulating leptin did not associate with changes in tumor burden. Uniquely, tumors in mice that received VSG displayed elevated inflammation and checkpoint ligand PD-L1. Further, mice that received VSG had reduced tumor infiltrating T lymphocytes suggesting an ineffective anti-tumor microenvironment. VSG-associated elevation of PD-L1 prompted us to next investigate the efficacy of immune checkpoint inhibitors in lean, obese, and formerly obese mice that lost weight by VSG or weight matched controls. While obese mice were resistant to immunotherapy, anti-PD-L1 potently impaired tumor progression after VSG through improved anti-tumor immunity. Thus, in formerly obese mice, surgical weight loss followed by immunotherapy reduced breast cancer burden. Further studies are necessary to determine how bariatric surgery sensitizes tumors to immune checkpoint inhibition.

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Section: Discussionsupporting

confidence: 91%

Response to immune checkpoint blockade improved in pre-clinical model of breast cancer after bariatric surgery

Sipe

Chaib

Korba

et al. 2022

Preprint

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“…This is consistent with the established role of activated brown and beige fat 33 but no causal link was established. In this regard, preferential uptake of 18-FDG into inguinal and epidydimal WAT after VSG in rats may help explain the surgery-induced improvement in glucose regulation but, in this case, BAT was not examined 34 . These data are consistent with those derived from clinical studies where elevation of activated BAT 21, 35 and BeAT 36, 37 occur after VSG, again contemporaneously with improved glucose regulation 21 .…”

Section: Discussionmentioning

confidence: 99%

Mechanisms underlying the efficacy of a rodent model of vertical sleeve gastrectomy — a focus on energy expenditure

Stefanidis

Lee

Greaves

et al. 2022

Preprint

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Background and aims: Bariatric surgery remains the only effective and durable treatment option for morbid obesity. Vertical Sleeve Gastrectomy (VSG) is currently the most widely performed of these surgeries primarily because of its proven efficacy in generating rapid onset weight loss, improved glucose regulation and reduced mortality compared with other invasive procedures. VSG is associated with reduced appetite, however, the relative importance of energy expenditure to VSG-induced weight loss and changes in glucose regulation, particularly that in brown adipose tissue (BAT), remains unclear. The aim of this study is to investigate the role of BAT thermogenesis in the efficacy of VSG in a rodent model. Methods: Diet-induced obese male Sprague-Dawley rats were either sham-operated, underwent VSG surgery or were pairfed to the food consumed by the VSG group. Rats were also implanted with biotelemetry devices between the interscapular lobes of BAT to assess local changes in BAT temperature as a surrogate measure of thermogenic activity. Metabolic parameters including food intake, body weight and changes in body composition were assessed. To further elucidate the contribution of energy expenditure via BAT thermogenesis to VSG-induced weight loss, a separate cohort of lean rats underwent complete excision of the interscapular BAT (iBAT lipectomy) or chemical denervation using 6-hydroxydopamine (6-OHDA). To localize glucose uptake in specific tissues, an oral glucose tolerance test was combined with an intraperitoneal injection of 2 deoxy-D-glucose (2DG)-14C, administered intraperitoneally. Transneuronal viral tracing was used to identify 1) sensory neurons directed to the stomach or small intestine (H129-RFP) or 2) chains of polysynaptically linked neurons directed to BAT (PRV-GFP) in the same animals. Results: Following VSG, there was a rapid reduction in body weight that was associated with reduced food intake, elevated BAT temperature and improved glucose regulation. Rats that underwent VSG had elevated glucose uptake into BAT compared to sham operated animals as well as elevated gene markers related to increased BAT activity (Ucp1, Dio2, Cpt1b, Cox8b, Ppargc) and markers of increased browning of white fat (Ucp1, Dio2, Cited1, Tbx1, Tnfrs9). Both iBAT lipectomy and 6-OHDA treatment significantly attenuated the impact of VSG on changes in body weight and adiposity in lean animals. In addition, surgical excision of iBAT following VSG significantly reversed VSG-mediated improvements in glucose tolerance, an effect that was independent of circulating insulin levels. Viral tracing studies highlight a patent neural link between the gut and BAT that include groups of premotor BAT-directed neurons in the dorsal raphe and raphe pallidus. Conclusion: Collectively, these data support a role for BAT in mediating the metabolic sequelae, particularly the improvement in glucose regulation following VSG surgery and highlight the need to better understand the contribution from this tissue in human patients.

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“…To understand the mechanisms underlying VSG-induced improvement in glucose homeostasis, Harris et al evaluated tissue-specific glucose uptake using 18 fluorodeoxyglucose positron emission tomography/ computed tomography in a mouse model. They found VSG resulted in a significant increase in glucose uptake by visceral adipose tissue, which was associated with the upregulation of transcripts involved in energy metabolism, suggesting increased glucose use in adipose tissue after VSG [77]. However, these results were from a nonobese mouse model and need to be validated in obese mouse models as well as in humans.…”

Section: Glucose Metabolismmentioning

confidence: 99%

Recent advances in the mechanisms underlying the beneficial effects of bariatric and metabolic surgery

Song

2021

Surgery for Obesity and Related Diseases

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Bariatric and metabolic surgery (BMS) is the most effective treatment for obesity, type 2 diabetes and co-morbidities, including nonalcoholic fatty liver disease and nonalcoholic steatohepatitis. The beneficial effects of BMS are beyond the primary goal of gastric restriction and nutrients malabsorption. Roux-en-Y gastric bypass and vertical sleeve gastrectomy are the 2 most commonly performed procedures of BMS. Both surgeries lead to physiologic changes in gastrointestinal tract; subsequently alter bile acids pool and composition, gut microbial activities, gut hormones, and circulating exosomes; and ultimately contribute to the improved glycemic control, insulin sensitivity, lipid metabolism, energy expenditure, and weight loss. The mechanisms underlying the benefits of BMS likely involve the bile acid-signaling pathway mediated mainly by nuclear farnesoid X receptor and the membrane Takeda G protein-coupled receptor, bile acids-gut microbiota interaction, and exosomes. In this review, we focus on recent advances in potential mechanisms and aim to learn novel insights into the molecular mechanisms underlying metabolic disorders.

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

Cited by 3 publications

References 72 publications

Response to immune checkpoint blockade improved in pre-clinical model of breast cancer after bariatric surgery

Response to immune checkpoint blockade improved in pre-clinical model of breast cancer after bariatric surgery

Mechanisms underlying the efficacy of a rodent model of vertical sleeve gastrectomy — a focus on energy expenditure

Recent advances in the mechanisms underlying the beneficial effects of bariatric and metabolic surgery

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