Pathology of Congenital Generalized Lipodystrophy in Agpat2^–/– Mice

Abstract

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 b-cell loss and that adipocyte-derived factors help regulate total b-cell mass.

High-throughput screening of mouse gene knockouts identifies established and novel skeletal phenotypes

“…274,275 Two of four mice Agpat2 KO mice examined histologically at ten days of age had spontaneous proximal femur (hip) fractures. 276 No HTS bone phenotypes were observed in heterozygous mutant mice.…”

How lipid droplets “TAG” along: Glycerolipid synthetic enzymes and lipid storage

“…Thus, defects in differentiation may be the fundamental defect in Agpat2 −/− preadipocytes, prior to a need for TAG synthesis. There is also evidence that brown adipose tissue of Agpat2 −/− mice exhibits massive necrosis and is ablated in young mice, whereas white adipose tissue undergoes apoptosis and/or necrosis as the mice age [96,97]. White adipose tissue in newborn Agpat2 −/− mice has several ultrastructural abnormalities, including an absence of caveolae, aberrant mitochondria, and an accumulation of autophagic organelles [96].…”

“…Additionally, hepatic steatosis in Agpat2 −/− mice cannot be reversed by adenoviral expression of AGPAT2 directly in liver, suggesting that steatosis does not result from local AGPAT deficiency, but rather is a secondary result of the insulin resistance that occurs due to lipodystrophy and reduced leptin levels [99,100]. In addition to hepatic abnormalities, Agpat2 −/− mice develop pancreatic islet hypertrophy, possibly in response to chronic hyperglycemia [97]. …”

Expression of seipin in adipose tissue rescues lipodystrophy, hepatic steatosis and insulin resistance in seipin null mice

“…Loss of adipose tissue in lipodystrophy is associated with increased prevalence of insulin resistance, dyslipidemia, hypertension, hepatic steatosis and increased predisposition to atherosclerosis [18]. In recent years, many lipodystrophic mouse models (A-ZIP/F mice [19], aP2-nSREBP-1c mice [20], AGPAT2 KO mice [21], aP2-PPARg KO mice [22] etc) have been generated. All of them suffered completely or partially loss of adipose tissue, insulin resistance and hepatic steatosis.…”

“…AGPAT2 deficient mice also suffer severe lipodystrophy and hepatic steatosis [21]. Because AGPAT2 is highly expressed in the liver, Agarwal et al have generated liver specific AGPAT1 or AGPAT2 reconstituted in AGPAT2-KO mice [27].…”