Sleeve Gastrectomy Suppresses Hepatic Glucose Production and Increases Hepatic Insulin Clearance Independent of Weight Loss

Abstract

Bariatric operations induce weight loss, which is associated with an improvement in hepatic steatosis and a reduction in hepatic glucose production. It is not clear whether these outcomes are entirely due to weight loss, or whether the new anatomy imposed by the surgery contributes to the improvement in the metabolic function of the liver. We performed vertical sleeve gastrectomy (VSG) on obese mice provided with a high-fat high-sucrose diet and compared them to diet and weight-matched sham-operated mice (WMS). At 40 days after surgery, VSG-operated mice displayed less hepatic steatosis compared with WMS. By measuring the fasting glucose and insulin levels in the blood vessels feeding and draining the liver, we showed directly that hepatic glucose production was suppressed after VSG. Insulin levels were elevated in the portal vein, and hepatic insulin clearance was elevated in VSG-operated mice. The hepatic expression of genes associated with insulin clearance was upregulated. We repeated the experiment in lean mice and observed that portal insulin and glucagon are elevated, but only insulin clearance is increased in VSG-operated mice. In conclusion, direct measurement of glucose and insulin in the blood entering and leaving the liver shows that VSG affects glucose and insulin metabolism through mechanisms independent of weight loss and diet.

Sleeve Gastrectomy Reduces Glycemia but Does Not Affect Cognitive Impairment in Lean 5xFAD Mice

“…To date, there is no reliable rodent model for sporadic AD which is the more common form of AD. We and others have shown that SG is not effective in maintaining weight loss in early-onset genetic obesity modeled by db/db mice or Melanocortin 4 Receptor null rats, yet it is effective in obesity models induced through a calorie-rich diet ( Hatoum et al, 2012 ; Abu-Gazala et al, 2018 ; Ben-Haroush Schyr et al, 2021 ). Our data, therefore, do not reject the hypothesis that SG can have a weight loss independent effect in sporadic AD in patients, and that this effect cannot overcome the strong genetic basis of disease in 5xFAD mice.…”

“…Clinical and animal studies demonstrated that these effects are mediated by weight loss dependent and independent mechanisms ( Chambers et al, 2011 ; Sjostrom, 2013 ; Douros et al, 2019 ; Aminian et al, 2021 ; Azulai et al, 2021 ). Some of the positive and negative effects of bariatric surgery were observed also in lean rodents, suggesting that the metabolic and endocrine state induced by surgery can have beneficial or detrimental physiolgoical effects ( Li et al, 2019 ; Ben-Haroush Schyr et al, 2021 ; Akalestou et al, 2022a ; Hefetz et al, 2022 ). Obesity is associated with cognitive decline and is a risk factor for AD ( Ahlskog et al, 2011 ; Ngandu et al, 2015 ; Spitznagel et al, 2015 ; Rochette et al, 2016 ; Stephen et al, 2017 ), and bariatric surgery was shown in most studies to improve cognitive function in patients with obesity ( Miller et al, 2013 ; Alosco et al, 2014a , b ; Spitznagel et al, 2015 ; Rochette et al, 2016 ; Thiara et al, 2017 ; Prehn et al, 2020 ; Morledge and Pories, 2021 ).…”

Regulation of Insulin Clearance by Non-Esterified Fatty Acids

“…This supports the findings that lipolysis-derived NEFA repress hepatic CEACAM1 expression, consistent with findings in rats exposed to acute intralipid infusion [ 72 ]. Accordingly, hepatic insulin clearance and insulin sensitivity were restored in diet-induced mouse models of obesity undergoing Vertical Sleeve Gastrectomy in parallel to inducing the expression of CEACAM1 and IDE, and independently of weight loss [ 96 ].…”

Inhibition of somatostatin enhances the long-term metabolic outcomes of sleeve gastrectomy in mice

“…Sleeve gastrectomy (SG) is a common bariatric surgery wherein most of the stomach is excised along the greater curvature to produce a sleeve-shaped stomach. This surgery leads to weight loss and improved glycemic control, and alleviation of metabolic disorders in most patients and rodent models (19)(20)(21)(22)(23). SG affects the microbiome, the levels of bile acids and other metabolites in the blood, and leads to a post-prandial increase in GI and pancreatic hormones such as Glp1 and insulin and modulates processes that regulate systemic metabolism (24)(25)(26)(27).…”