Increased β-Oxidation but No Insulin Resistance or Glucose Intolerance in Mice Lacking Adiponectin

Ke Ma,Agatha Cabrero,Pradip K Saha,Hideto Kojima,Lan Li,Benny Hung-Junn Chang,Antoni Paul,Lawrence Chan

doi:10.1074/jbc.c200362200

Abstract

Previous reports showed that recombinant fragments of adiponectin (adipo) displayed pharmacological effects when injected into rodents, but the relevance of these observations to the physiological function of adipo is unclear. We generated Adipo(-/-) mice by gene targeting. Adipo(-/-) mice are fertile with normal body and fat pad weights. Plasma glucose and insulin levels of Adipo(-/-) and Adipo(+/+) mice are similar under fasting conditions and during an intraperitoneal glucose tolerance test (GTT). Insulin tolerance test (ITT) also produces similar plasma glucose and insulin levels in the two groups of mice. Hyperinsulinemic-euglycemic clamp analysis showed that Adipo(-/-) and Adipo(+/+) mice have similar glucose infusion rates to maintain a similar serum glucose. High-fat diet feeding for 7 months led to similar weight gain and similar GTT and ITT responses. We next measured beta-oxidation and found it to be significantly increased in muscle and liver of Adipo(-/-) mice. In conclusion, our study indicates that absence of adipo causes increased beta-oxidation but does not cause glucose intolerance or insulin resistance in mice.

Highlights

Plasma glucose and insulin levels of Adipo؊/؊ and Adipo؉/؉ mice are similar under fasting conditions and during an intraperitoneal glucose tolerance test (GTT)
To elucidate the in vivo role of adipo, we generated AdipoϪ/Ϫ mice by gene targeting. We found that these mice had no glucose intolerance or insulin resistance under basal conditions or even after they were fed a high-fat diet for 7 months
Like their F6 wild-type littermates, both male and female F6 AdipoϪ/Ϫ mice had normal fasting plasma glucose and insulin levels; there was no difference in these parameters during a 2-h GTT (Fig. 2, A and B)

Summary

EXPERIMENTAL PROCEDURES

Generation of Targeted Mice—We used a replacement-type targeting vector constructed from a mouse 129/Sv strain bacterial artificial chromosome genomic clone and R1 ES cell line for gene targeting (Fig. 1A). Transfection and ES cell clone selection were as described [9]. Northern Blot and Immunoblot Analysis—Northern blots were performed on total RNA isolated from white and brown adipose tissue using a 32P-labeled mouse full-length cDNA probe as described [9, 10]. Immunoblotting were performed as described previously using 3 ␮l of plasma [9]. Hyperinsulinemic-Euglycemic Clamp—We measured in vivo glucose utilization by the hyperinsulinemic-euglycemic clamp method as described previously [12] with slight modification. Total body glucose infusion rate was calculated as described [12]. ␤-Oxidation—For quantitation of ␤-oxidation, we measured [14C]CO2 production from [1-14C]palmitic acid in isolated soleus muscle as described [13] and in liver homogenates as described [14]

RESULTS

DISCUSSION

Fatty acid oxidation