Obesity promotes insulin resistance associated with liver inflammation, elevated glucose production, and type 2 diabetes. Although insulin resistance is attenuated in genetic mouse models that suppress systemic inflammation, it is not clear whether local resident macrophages in liver, denoted Kupffer cells (KCs), directly contribute to this syndrome. We addressed this question by selectively silencing the expression of the master regulator of inflammation, NF-kappaB, in KCs in obese mice. We used glucan-encapsulated small interfering RNA particles (GeRPs) that selectively silence gene expression in macrophages in vivo. Following intravenous injections, GeRPs containing siRNA against p65 of the NF-kappaB complex caused loss of NF-kappaB p65 expression in KCs without disrupting NF-kappaB in hepatocytes or macrophages in other tissues. Silencing of NF-kappaB expression in KCs in obese mice decreased cytokine secretion and improved insulin sensitivity and glucose tolerance without affecting hepatic lipid accumulation. Importantly, GeRPs had no detectable toxic effect. Thus, KCs are key contributors to hepatic insulin resistance in obesity and a potential therapeutic target for metabolic disease.

BACKGROUND: Obesity is a strong risk factor for resistance to insulin-mediated glucose disposal, a precursor of type 2 diabetes and other disorders. However, not all obese individuals are insulin resistant. We sought to identify the molecular pathways that might cause obesity-associated insulin resistance in humans by studying the morbidly obese who were insulin sensitive versus insulin resistant, thereby eliminating obesity as a variable. METHODS: Combining gene expression profiling with computational approaches, we determined the global gene expression signatures of omental and subcutaneous adipose tissue samples obtained from similarly obese patients undergoing gastric bypass surgery. RESULTS: Gene sets related to chemokine activity and chemokine receptor binding were identified as most highly expressed in the omental tissue from insulin-resistant compared with insulin-sensitive subjects, independent of the body mass index. These upregulated genes included chemokines (C-C motif) ligand 2, 3, 4, and 18 and interleukin-8/(CC-X motif) ligand 8 and were not differentially expressed in the subcutaneous adipose tissues between the 2 groups of subjects. Insulin resistance, but not the body mass index, was associated with increased macrophage infiltration in the omental adipose tissue, as was adipocyte size, in these morbidly obese subjects. CONCLUSION: Our findings have demonstrated that inflammation of the omental adipose tissue is strongly associated with insulin resistance in human obesity even in subjects with similar body mass index values. Published by Elsevier Inc. All rights reserved.

HYPOTHESIS: The use of smaller instruments during laparoscopic cholecystectomy (LC) has been proposed to reduce postoperative pain and improve cosmesis. However, despite several recent trials, the effects of the use of miniaturized instruments for LC are not well established. We hypothesized that LC using miniports (M-LC) is safe and produces less incisional pain and better cosmetic results than LC performed conventionally (C-LC). DESIGN: A patient- and observer-blinded, randomized, prospective clinical trial. SETTING: A tertiary care, university-based hospital. PATIENTS: Seventy-nine patients scheduled for an elective LC who agreed to participate in this trial were randomized to undergo surgery using 1 of the 2 instrument sets. The criteria for exclusion were American Society of Anesthesiologists class III or IV, age older than 70 years, liver or coagulation disorders, previous major abdominal surgical procedures, and acute cholecystitis or acute choledocholithiasis. INTERVENTION: Laparoscopic cholecystectomy performed with either conventional or miniaturized instruments. MAIN OUTCOME MEASURES: Patients' age, sex, operative time, operative blood loss, intraoperative complications, early and late postoperative incisional pain, and cosmetic results. RESULTS: Thirty-three C-LCs and 34 M-LCs were performed and analyzed. There were 8 conversions (24%) to the standard technique in the M-LC group. No intraoperative or major postoperative complications occurred in either group. The average incisional pain score on the first postoperative day was significantly less in the M-LC group (3.9 vs 4.9; P = .04). No significant differences occurred in the mean scores for pain on postoperative days 3, 7, and 28. However, 90% of patients in the M-LC group and only 74% of patients in the C-LC group had no pain (visual analog scale score of 0) at 28 days postoperatively (P = .05). Cosmetic results were superior in the M-LC group according to both the study nurse's and the patients' assessments (38.9 vs 28.9; P<.001, and 38.8 vs 33.4; P = .001, respectively). CONCLUSIONS: Laparoscopic cholecystectomy can be safely performed using 10-mm umbilical, 5-mm epigastric, 2-mm subcostal, and 2-mm lateral ports. The use of mini-laparoscopic techniques resulted in decreased early postoperative incisional pain, avoided late incisional discomfort, and produced superior cosmetic results. Although improved instrument durability and better optics are needed for widespread use of miniport techniques, this approach can be routinely offered to many properly selected patients undergoing elective LC.