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

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.

Early changes in immune cell metabolism and function are a hallmark of sleeve gastrectomy: a prospective human study

“…We observed a general downregulation in cytokine pathways along with an upregulation in gene expressions of several immunoglobulins. This is in line with a number of human and animals studies that have also demonstrated a rise in circulating and adipose tissue immunoglobulins along with a change the regulatory function of B lymphocytes following bariatric surgery 47,48 . These modifications in the adaptive immune system may explain the improvements in autoimmune or immune-mediated diseases detected following bariatric surgery 35,49 .…”

“…Taken together, our data suggest that LSG may have a profound effect on immune cells through the modulation of their own metabolic processes. We have previously published data that describes changes within metabolic and immune pathways in visceral adipose tissue following LSG using rodent model 47 . However, to our knowledge, this complex post-LSG relationship between immunity remodeling and cell metabolism within human immune cells has not been previously described.…”

Do Bariatric Surgeries Enhance Brown/Beige Adipose Tissue Thermogenesis?

“…Remarkably, this revealed that VSG significantly increased 18 F-FDG uptake in iWAT and eWAT compared to sham surgery despite similar body weights and energy expenditure determined by indirect calorimetry between groups. Additionally, VSGoperated mice exhibited improved oral glucose tolerance and increased systemic carbohydrate metabolism (118). Since 18 F-FDG uptake by iWAT is increased by beta 3 adrenergic receptor agonist-induced and cold-induced browning (39), these findings provide further functional evidence of iWAT browning after VSG and novel evidence of eWAT browning and suggest that this contributes to improved glycaemic control but not to energy expenditure changes post-operatively.…”

“…This could potentially contribute to reduced methyltransferase activity of PRC2, leading to reduced lysine 27 trimethylation of histone H3 at the Ucp1 and Pgc1alpha promoters, thereby disinhibiting their transcription (119). It would be interesting in future studies to perform similar experiments as those of Harris et al (118) on mice at later timepoints after VSG to assess its long-term effects on whole-body energy and glucose balance in relation to brown and beige adipose tissue thermogenesis.…”

Single-cell Chromatin Accessibility and Lipid Profiling Reveals a Metabolic Shift in Adipocytes Induced by Bariatric Surgery

“…Reduced fat mass after VSG normalizes leptin levels, which can lead to reduced food intake. Metabolic shifts in SAT and VAT adipose tissue have been reported after VSG (Harris et al, 2020;Jahansouz et al, 2018). One study found increased lipolysis, lipid oxidation, and thermogenic gene expression in SAT from human patients.…”