Angiotensin-converting enzyme inhibition reverses diet-induced obesity, insulin resistance and inflammation in C57BL/6J mice

Abstract

Aim: Angiotensin-converting enzyme (ACE) inhibition can reduce the body weight of mice maintained on a high-fat diet. The current study examined the effect of the ACE inhibitor, captopril (CAP), on the reversal of diet-induced obesity (DIO), insulin resistance and inflammation in mice. Materials and methods: DIO was produced in C57BL/6J male mice (n ¼ 30) by maintaining animals on a high-fat diet (w/w 21% fat) for 12 weeks. During the subsequent 12-week treatment period, the animals were allowed access to the high-fat diet and either water containing CAP (0.05 mg ml À1 ) or plain tap water (CON, control). Results: From the first week of treatment, food intake and body weight decreased in CAP-treated mice compared with CON mice. Both peripheral insulin sensitivity and hepatic insulin sensitivity were improved in CAP-treated mice compared with CON mice. CAP-treated mice had decreased absolute and relative liver and epididymal fat weights compared with CON mice. CAP-treated mice had higher plasma adiponectin and lower plasma leptin levels than CON mice. Relative to CON mice, CAP-treated mice had reduced adipose and skeletal muscle monocyte chemoattractant protein 1 (MCP-1), adipose interleukin-6 (IL-6), toll-like receptor 4 (TLR4) and uncoupling protein 2 (UCP2) mRNA expressions. Furthermore, CAP-treated mice had increased peroxisome proliferator-activated receptor-g coactivator-1a (PGC-1a), long chain acyl-CoA dehydrogenase (LCAD), hormone sensitive lipase (HSL) and decreased lipoprotein lipase (LPL) mRNA expressions in the liver. Conclusion:The results of the current study indicate that in mice with DIO, CAP treatment reduced food intake and body weight, improved insulin sensitivity and decreased the mRNA expression of markers of inflammation. Thus, CAP may be a viable treatment for obesity, insulin resistance and inflammation.

Effect of peripherally administered leptin antagonist on whole body metabolism and bone microarchitecture and biomechanical properties in the mouse

“…It seems that one of the major differences between DIO and leptin signalingdeficient obesity due to PEG-SMLA treatment is the inflammatory condition. Circulating inflammatory cytokines are higher in DIO compared with normal subjects (18,53,59,69). With respect to leptin signaling, we showed that chronic inflammation is alleviated in leptin antagonist-treated mice (26,27); this might explain the differences found in bone phenotype between the two models.…”

“…In contrast, in ob/ob mice, LXR␣ expression increased 1.3-fold (78). LPL gene expression in the liver of mice under a HFD increased 1.2-to twofold (29,69), whereas with the PEG-SMLA treatment its expression was decreased after 4 wk. RIFL is a prolipogenic gene that is highly induced during adipocyte differentiation, indicating enhanced adipogenesis, which is consistent with the expression of other genes responsible for adipogenesis in our study.…”

“…We limited our comparison to C57BL/6J mice, a strain that is known to be susceptible to diabetes on HFDs and is the genetic background for the ob/ob model; the results are compiled in Supplemental Table S2. The absolute weight gain in both HFD and PEG-SMLA treatments was similar, but the latter was achieved in 2-3 wk, in contrast to the much longer period required with a HFD (8,13,14,34,37,39,40,55,58,64,69), and the outcome could be rapidly reversed (27). However, the feeding behavior was different.…”

“…A comparison of two inflammatory cytokines showed a similar pattern. IL-6 increased 1.4-to fivefold in HFD after 5-24 wk (18,53,69), whereas with the PEG-SMLA treatment it increased 1.6-fold after 12 wk. TNF␣ increased two-to fourfold after 5-15 wk …”

Effect of Obesity on Circulating Adipokines and Their Expression in Omental Adipose Tissue of Female Bariatric Surgery Patients

“…The circulating levels of ACE are unchanged in obesity as is its gene expression in adipose tissue of humans but there is a positive correlation with blood pressure . It has been difficult to get evidence for a key role of ACE but recently it was reported that ACE inhibition using captopril treatment of mice on a high fat diet reduced the extent of obesity and the expression of markers of inflammation in murine adipose tissue (Premaratna et al 2011). Lee at al (2008a) reported that in obese rats, angiotensin receptor blockade reduced insulin resistance by modification of adipose tissue metabolism.…”