Tissue-specific disruption of <i>Kbtbd2</i> uncovers adipocyte-intrinsic and -extrinsic features of the <i>teeny</i> lipodystrophy syndrome.

Abstract

Loss of KBTBD2 in all tissues causes the <i>teeny</i> phenotype, characterized by insulin resistance with late failure of insulin production, severe hyperglycemia/diabetes, lipodystrophy, hepatosteatosis, and growth retardation. KBTBD2 maintains insulin sensitivity in adipocytes by restricting the abundance of p85α. However, the possible physiological contribution or contributions of KBTBD2 have not yet been examined in other tissues. Here we show that mice with an adipocyte-specific knockout of <i>Kbtbd2</i> accumulate p85α in white and brown adipose tissues, causing insulin resistance, moderate rather than severe hyperglycemia, sustained hyperinsulinemia without late failure of insulin production, and lipodystrophy leading to ectopic lipid accumulation in the liver. Adipocyte-extrinsic insulin resistance was observed in liver and muscle. None of these abnormalities were observed in liver- or muscle-specific <i>Kbtbd2</i> knockout mice. Mice with <i>Kbtbd2</i> knockout in adipocytes, liver, and muscle all showed normal growth, suggesting that KBTBD2 may be necessary to ensure IGF1 signaling in other tissues, notably bone. While much of the <i>teeny</i> phenotype results from loss of KBTBD2 in adipocytes, some features are adipocyte-extrinsic.