Pathology of congenital generalized lipodystrophy in Agpat2-/- mice.
Congenital generalized lipodystrophy (CGL) comprises a heterogeneous group of rare diseases associated with partial or total loss of adipose tissue. Of these, autosomal recessive Berardinelli-Seip congenital lipodystrophy (BSCL) is characterized by the absence of metabolically active subcutaneous and visceral adipose tissues. Metabolic abnormalities associated with lipodystrophy include insulin resistance, hypertriglyceridemia, hepatic steatosis, and diabetes. One form of BSCL has been linked to genetic mutations affecting the lipid biosynthetic enzyme 1-acyl-sn-glycerol 3-phosphate O-acyltransferase 2 (AGPAT2), which is highly expressed in adipose tissue. Precisely how AGPAT2 deficiency causes lipodystrophy remains unresolved, but possible mechanisms include impaired lipogenesis (triglyceride synthesis and storage), blocked adipogenesis (differentiation of preadipocytes to adipocytes), or apoptosis/necrosis of adipocytes. Agpat2(-/-) mice share important pathophysiologic features of CGL previously reported in humans. However, the small white adipose tissue (WAT) depots consisting largely of amoeboid adipocytes with microvesiculated basophilic cytoplasm showed that adipogenesis with deficient lipogenesis was present in all usual locations. Although well-defined lobules of brown adipose tissue (BAT) were present, massive necrosis resulted in early ablation of BAT. Although necrotic or apoptotic adipocytes were not detected in WAT of 10-day-old Agpat2(-/-), the absence of adipocytes in aged mice indicates that these cells must undergo necrosis/apoptosis at some point. Another significant finding in aged lipodystrophic mice was massive pancreatic islet hypertrophy in the face of chronic hyperglycemia, which suggests that glucotoxicity is insufficient by itself to cause β-cell loss and that adipocyte-derived factors help regulate total β-cell mass.
Lexicon Pharmaceuticals, Inc, Pathology Department, The Woodlands, TX 77381-1160, USA. pvogel@lexpharma.com
P
P
Vogel
R
R
Read
G
G
Hansen
J
J
Wingert
C M
CM
Dacosta
L M
LM
Buhring
M
M
Shadoan
D051103:1-Acylglycerol-3-Phosphate O-Acyltransferase / Q000235:genetics / Q000378:metabolism*; D000375:Aging; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D005951:Glucose Tolerance Test; D006529:Hepatomegaly / Q000235:genetics / Q000473:pathology; D007328:Insulin / Q000378:metabolism; D050356:Lipid Metabolism / Q000235:genetics; D008060:Lipodystrophy / Q000151:congenital* / Q000235:genetics / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout
D001786:Blood Glucose; D007328:Insulin; D051103:1-Acylglycerol-3-Phosphate O-Acyltransferase