Mice lacking angiotensin-converting enzyme have increased energy expenditure, with reduced fat mass and improved glucose clearance

Abstract

In addition to its role in the storage of fat, adipose tissue acts as an endocrine organ, and it contains a functional renin-angiotensin system (RAS). Angiotensin-converting enzyme (ACE) plays a key role in the RAS by converting angiotensin I to the bioactive peptide angiotensin II (Ang II). In the present study, the effect of targeting the RAS in body energy homeostasis and glucose tolerance was determined in homozygous mice in which the gene for ACE had been deleted (ACE(-/-)) and compared with wild-type littermates. Compared with wild-type littermates, ACE(-/-) mice had lower body weight and a lower proportion of body fat, especially in the abdomen. ACE(-/-) mice had greater fed-state total energy expenditure (TEE) and resting energy expenditure (REE) than wild-type littermates. There were pronounced increases in gene expression of enzymes related to lipolysis and fatty acid oxidation (lipoprotein lipase, carnitine palmitoyl transferase, long-chain acetyl CoA dehydrogenase) in the liver of ACE(-/-) mice and also lower plasma leptin. In contrast, no differences were detected in daily food intake, activity, fed-state plasma lipids, or proportion of fat excreted in fecal matter. In conclusion, the reduction in ACE activity is associated with a decreased accumulation of body fat, especially in abdominal fat depots. The decreased body fat in ACE(-/-) mice is independent of food intake and appears to be due to a high energy expenditure related to increased metabolism of fatty acids in the liver, with the additional effect of increased glucose tolerance.

Fig. 1.

ACE deficiency altered body weight, fat mass, and distribution. (A and B) The ACE^−/− mice (open bars) had significantly lower body weight (A) and proportion of body fat (B) than ACE^+/+ mice (filled bars). The values are mean ± SEM (n = 14 per group); ∗, P < 0.05. (C) Proton density-weighted axial MRI images across the body of ACE^+/+ and ACE^−/− mice. Bright, white areas denote fat. The white arrowhead indicates the larger android fat stores in ACE^+/+ mice.

Fig. 2.

After glucose load, ACE^−/− mice had faster clearance than ACE^+/+ mice, blood glucose was significantly lower at 60 and 120 min, with a reduced AUC. n = 6 per group. ∗, P < 0.05 vs. ACE^+/+ mice; †, P < 0.05 vs. baseline.

Fig. 3.

The RQ of ACE^−/− mice did not differ from ACE^+/+ mice either under fed-state conditions or during fasting. Fasting resulted in a significantly lower RQ in both ACE^−/− and ACE^+/+ mice. n = 6 per group. †, P < 0.05 vs. baseline.

Fig. 4.

Under fed-state conditions, ACE^−/− mice had a higher TEE (A) and REE (B) compared with ACE^+/+. Fasting resulted in lower TEE and REE in both ACE^−/− and ACE^+/+ mice. When fasted ACE^−/− mice had significantly lower TEE and REE than ACE^+/+ mice. n = 6 per group. ∗, P < 0.05 vs. ACE^+/+ mice; †, P < 0.05 vs. baseline.

Fig. 5.

Running wheel distance (n = 5 per group) (A), average speed (n = 5 per group) (B), and general locomotor activity (n = 6 per group) (C) were not affected in ACE^−/− mice. General locomotor activity was unaffected by fasting.

Fig. 6.

A scheme of energy balance in ACE^−/− mice, where energy intake as food is normal, but the equilibrium between energy storage and utilization is in favor of the latter. The increases in whole-body energy expenditure (measured by indirect calorimetry) and hepatic fatty acid oxidation dissipate ingested calories, reducing energy storage in adipose tissue and lowering body fat mass.