Itm2a silencing rescues lamin A mediated inhibition of 3T3-L1 adipocyte differentiation

Abstract

Dysregulation of adipose tissue metabolism is associated with multiple metabolic disorders. One such disease, known as Dunnigan-type familial partial lipodystrophy (FPLD2) is characterized by defective fat metabolism and storage. FPLD2 is caused by a specific subset of mutations in the LMNA gene. The mechanisms by which LMNA mutations lead to the adipose specific FPLD2 phenotype have yet to be determined in detail. We used RNA-Seq analysis to assess the effects of wild-type (WT) and mutant (R482W) lamin A on the expression profile of differentiating 3T3-L1 mouse preadipocytes and identified Itm2a as a gene that was upregulated at 36 h post differentiation induction in these cells. In this study we identify Itm2a as a novel modulator of adipogenesis and show that endogenous Itm2a expression is transiently downregulated during induction of 3T3-L1 differentiation. Itm2a overexpression was seen to moderately inhibit differentiation of 3T3-L1 preadipocytes while shRNA mediated knockdown of Itm2a significantly enhanced 3T3-L1 differentiation. Investigation of PPARγ levels indicate that this enhanced adipogenesis is mediated through the stabilization of the PPARγ protein at specific time points during differentiation. Finally, we demonstrate that Itm2a knockdown is sufficient to rescue the inhibitory effects of lamin A WT and R482W mutant overexpression on 3T3-L1 differentiation. This suggests that targeting of Itm2a or its related pathways, including autophagy, may have potential as a therapy for FPLD2.

Metformin reduces saturated fatty acid-induced lipid accumulation and inflammatory response by restoration of autophagic flux in endothelial cells

“…Due to mitochondrial dysfunction, fatty acid utilization is impaired while glucose utilization is enhanced 61 . Therefore, the increased glucose utilization may stimulate the expression of ITM2A, which is a negative regulator of vacuolar ATPase (V-ATPase) 62 . Thus, V-ATPase may be inhibited by accumulated fatty acyl-CoA and the increased ITM2A, which causes the elevation of lysosomal pH.…”

Maternal high-fat diet programs white and brown adipose tissue lipidome and transcriptome in offspring in a sex- and tissue-dependent manner in mice

“…5b ). In SAT, we identified several X-linked DEG involved in adipogenesis and beiging processes ( Itm2a , Flna, Cited1, Arxes1/2 and cox7b ) [ 23 , 25 – 27 ] (Fig. 5c ).…”

Urinary Cell Transcriptome Profiling and Identification of ITM2A, SLAMF6, and IKZF3 as Biomarkers of Acute Rejection in Human Kidney Allografts

“… 24 Although research continues to support its role in the early stages of chondrogenic differentiation, 25 – 27 ITM2A is widely expressed, most prominently in the ovary, thyroid, fat, and lymph node. 28 ITM2A is implicated in a number of physiologic processes, ranging from adipogenesis and cell cycle arrest to calcium channel gene expression, 29 – 31 and in several diseases including Graves’ disease and ankylosing spondylitis. 32 – 34 …”