Opposing effects of reduced kidney mass on liver and skeletal muscle insulin sensitivity in obese mice.

Reduced kidney mass and/or function may result in multiple metabolic derangements, including insulin resistance. However, underlying mechanisms are poorly understood. Herein, we aimed to determine the impact of reduced kidney mass on glucose metabolism in lean and obese mice. To that end, 7-week-old C57BL/6J mice underwent uninephrectomy (UniNx) or sham operation. After surgery, animals were fed either a chow (standard) diet or a high-fat diet (HFD), and glucose homeostasis was assessed 20 weeks after surgery. Intraperitoneal glucose tolerance was similar in sham-operated and UniNx mice. However, insulin-stimulated glucose disposal in vivo was significantly diminished in UniNx mice, whereas insulin-stimulated glucose uptake into isolated skeletal muscle was similar in sham-operated and UniNx mice. Of note, capillary density was significantly reduced in skeletal muscle of HFD-fed UniNx mice. In contrast, hepatic insulin sensitivity was improved in UniNx mice. Furthermore, adipose tissue hypoxia-inducible factor 1α expression and inflammation were reduced in HFD-fed UniNx mice. Treatment with the angiotensin II receptor blocker telmisartan improved glucose tolerance and hepatic insulin sensitivity in HFD-fed sham-operated but not UniNx mice. In conclusion, UniNx protects from obesity-induced adipose tissue inflammation and hepatic insulin resistance, but it reduces muscle capillary density and, thus, deteriorates HFD-induced skeletal muscle glucose disposal.