Mesenteric visceral lipectomy using tissue liquefaction technology reverses insulin resistance and causes weight loss in baboons

Abstract

Background: Visceral obesity is associated with diabetogenic and atherogenic abnormalities, including insulin resistance and increased risk for cardiometabolic diseases and mortality. Rodent lipectomy studies have demonstrated a causal link between visceral fat and insulin resistance, yet human omentectomy studies have failed to replicate this metabolic benefit, perhaps owing to the inability to target the mesentery.

Objectives: We aimed to demonstrate that safe and effective removal of mesenteric fat could be achieved in obese insulin-resistant baboons using tissue liquefaction technology.

Setting: Southwest National Primate Research Center, San Antonio, Texas.

Methods: Tissue liquefaction technology has been developed to enable mesenteric visceral lipectomy (MVL) to be safely performed without disturbing the integrity of surrounding nerves and vessels in the mesentary. After an initial MVL optimization study (n = 3), we then performed MVL (n = 4) or sham surgery (n = 2) in a cohort of insulin-resistant baboons, and the metabolic phenotype was assessed via hyperinsulinemic-euglycemic clamps at baseline and 6 weeks later.

Results: MVL led to a 75% improvement in glucose disposal at 6-weeks follow-up (P = .01). Moreover, despite removing only an average of 430 g of mesenteric fat (~1% of total body mass), MVL led to a 14.4% reduction in total weight (P = .001). Thus, these data demonstrate that mesenteric fat can be safely targeted for removal by tissue liquefaction technology in a nonhuman primate, leading to substantial metabolic improvements, including reversal of insulin resistance and weight loss.

Conclusions: These data provide the first demonstration of successful adipose tissue removal from the mesentery in a mammal. Importantly, we have demonstrated that when MVL is performed in obese, insulin-resistant baboons, insulin resistance is reversed, and significant weight loss occurs. Therefore, trials performing MVL in humans with abdominal obesity and related metabolic sequelae should be explored as a potential clinical tool to ameliorate insulin resistance and treat type 2 diabetes.

Keywords: Hypophagia; Insulin-resistant baboons; Mesenteric fat; Metabolic improvement; Tissue liquefaction technology.

Copyright © 2018 American Society for Bariatric Surgery. Published by Elsevier Inc. All rights reserved.

Figures

Figure 1 Legend.. Surgical removal of MF by TLT.

(A) Bar graph indicates amount of MF removed during Phase I optimization studies (black bars; n=3) and Phase II efficacy studies (gray bars; n=4). (B) Image taken during a Phase II MVL procedure showing that TLT can successfully remove adipose tissue from the mesentery without causing damage to the vascular supply or to the mesenteric sheath. (C) Lipoaspirate collected in a canister with ∼500 g of mesenteric visceral fat tissue removed (after complete gravity separation).

Figure 2 Legend.. Baseline body mass predicts relative weight loss response to MVL.

Baseline body mass of baboons assigned to MVL ranged from 38.2kg to 51.2kg. As a group, MVL resulted in a significant amount of weight loss (14.4%) at 6 wks follow-up (see Table 2). However, closer examination of this response revealed that greater baseline body mass tended to positively predicted a greater weight loss response (R2=0.76; p=0.084) with the largest intervened animals (ID19975 body wt 51.2kg; ID18344 body wt 49.0kg) demonstrating the greatest relative weight loss, while the smaller animals (ID28420 body wt 44.6kg; ID27677 body wt 38.2kg) lost much less weight.

Figure 3 Legend.. Phenotypic characteristics of pair-fed animals assigned to Sham or MVL.

(A-B) To control for changes in food intake after MVL, Sham-operated animals (n=2) were pair-fed to animals assigned to MVL (n=2) over a 6wk period. (C-F) Body weight, fat mass, percentage fat, and waist circumference were all reduced in both animals 6 wks following MVL, but not in Sham controls.

Figure 4 Legend.. Metabolic characteristics of pair-fed animals assigned to Sham or MVL.

(A) Insulin action in male, insulin-resistant baboons was assessed at baseline and at 6 wks follow-up by hyperinsulinemic-euglycemic clamps, which demonstrated markedly enhanced Rd (198% improvement) following MVL, while pair-fed controls only demonstrated an increase of 12.4% from baseline. (B-C) Circulating insulin levels in pair-fed MVL vs Sham obese insulin-resistant baboons. MVL tended to reduce insulin levels and HOMA-IR in previously insulin-resistant animals. (D) Circulating leptin levels, which is predominantly produced by SC fat, were unaffected by MVL at follow-up. (E) Circulating adiponectin levels, which is a favorable marker of metabolic health, were increased at 6 wks follow up in both animals assigned to the MVL procedure.