Lipodystrophy, Diabetes and Normal Serum Insulin in PPARγ-Deficient Neonatal Mice

Peroxisome proliferator activated receptor gamma (PPAR gamma) is a pleiotropic ligand activated transcription factor that acts in several tissues to regulate adipocyte differentiation, lipid metabolism, insulin sensitivity and glucose homeostasis. PPAR gamma also regulates cardiomyocyte homeostasis and by virtue of its obligate role in placental development is required for embryonic survival. To determine the postnatal functions of PPAR gamma in vivo we studied globally deficient neonatal mice produced by epiblast-restricted elimination of PPAR gamma. PPAR gamma-rescued placentas support development of PPAR gamma-deficient embryos that are viable and born in near normal numbers. However, PPAR gamma-deficient neonatal mice show severe lipodystrophy, lipemia, hepatic steatosis with focal hepatitis, relative insulin deficiency and diabetes beginning soon after birth and culminating in failure to thrive and neonatal lethality between 4 and 10 days of age. These abnormalities are not observed with selective PPAR gamma 2 deficiency or with deficiency restricted to hepatocytes, skeletal muscle, adipocytes, cardiomyocytes, endothelium or pancreatic beta cells. These observations suggest important but previously unappreciated functions for PPAR gamma 1 in the neonatal period either alone or in combination with PPAR gamma 2 in lipid metabolism, glucose homeostasis and insulin sensitivity.