Not Enough Fat: Mouse Models of Inherited Lipodystrophy

Abstract

Lipodystrophies belong to the heterogenous group of syndromes in which the primary defect is a generalized or partial absence of adipose tissue, which may be congenital or acquired in origin. Lipodystrophy should be considered in patients manifesting the combination of insulin resistance (with or without overt diabetes), dyslipidemia and fatty liver. Lipodystrophies are classified according to the etiology of the disease (genetic or acquired) and to the anatomical distribution of adipose tissue (generalized or partial). The mechanism of adipose tissue loss is specific to each syndrome, depending on the biological function of the mutated gene. Mice models, together with cellular studies have permitted clarification of the mechanisms by which human mutations deeply compromise adipocyte homeostasis. In addition, rodent models have proven to be crucial in deciphering the cardiometabolic consequences of the lack of adipose tissue such as NAFLD, muscle insulin resistance and cardiomyopathy. More precisely, tissue-specific transgenic and knockout mice have brought new tools to distinguish phenotypic traits that are the consequences of lipodystrophy from those that are cell-autonomous. In this review, we discuss the mice models of lipodystrophy including those of inherited human syndromes of generalized and partial lipodystrophy. We present how these models have demonstrated the central role of white adipose tissue in energetic homeostasis in general, including insulin sensitivity and lipid handling in particular. We underscore the differences reported with the human phenotype and discuss the limit of rodent models in recapitulating adipose tissue primary default. Finally, we present how these mice models have highlighted the function of the causative-genes and brought new insights into the pathophysiology of the cardiometabolic complications associated with lipodystrophy.

Effect of β-Estradiol on Adipogenesis in a 3T3-L1 Cell Model of Prelamin A Accumulation

“…Knock-out murine models for LMNA have been developed as well as models with point variants. However, they do not appear to mimic human disorders [31,32]. Since most LMNA variants seem to occur in exon 8, Wojtanik et al created a murine model for R482Q.…”

Loss of phospholipase PLAAT3 causes a mixed lipodystrophic and neurological syndrome due to impaired PPARγ signaling

“…Such discrepancies are not unusual and, while there is no doubt on the usefulness of mouse models to study human LS, differences between human and murine fat distribution and lipid metabolism represent known limitations. (52,53) PLAAT3 is certainly also involved in various cellular processes in different tissues, with a potential key role in phospholipid membrane plasticity. Considering its high expression in the brain and peripheral nerves, as well as the neurological symptoms observed in patients, it would be worth designing dedicated studies to investigate its role in the human brain and the peripheral nervous system.…”

The building blocks of caveolae revealed: caveolins finally take center stage

“…Mutations in CAV1 are also linked to pulmonary arterial hypertension and lipodystrophies [ 20 , 26 , 103–115 ]. Two of the best-studied examples include heterozygous frameshift mutations in the C-terminal region of the protein, P158P and F160X [ 110–114 ] ( Figure 6 ).…”