Deficiency in ZMPSTE24 and resulting farnesyl–prelamin A accumulation only modestly affect mouse adipose tissue stores

Abstract

Zinc metallopeptidase STE24 (ZMPSTE24) is essential for the conversion of farnesyl–prelamin A to mature lamin A, a key component of the nuclear lamina. In the absence of ZMPSTE24, farnesyl–prelamin A accumulates in the nucleus and exerts toxicity, causing a variety of disease phenotypes. By ∼4 months of age, both male and female Zmpste24−/− mice manifest a near-complete loss of adipose tissue, but it has never been clear whether this phenotype is a direct consequence of farnesyl–prelamin A toxicity in adipocytes. To address this question, we generated a conditional knockout Zmpste24 allele and used it to create adipocyte-specific Zmpste24–knockout mice. To boost farnesyl–prelamin A levels, we bred in the “prelamin A–only” Lmna allele. Gene expression, immunoblotting, and immunohistochemistry experiments revealed that adipose tissue in these mice had decreased Zmpste24 expression along with strikingly increased accumulation of prelamin A. In male mice, Zmpste24 deficiency in adipocytes was accompanied by modest changes in adipose stores (an 11% decrease in body weight, a 23% decrease in body fat mass, and significantly smaller gonadal and inguinal white adipose depots). No changes in adipose stores were detected in female mice, likely because prelamin A expression in adipose tissue is lower in female mice. Zmpste24 deficiency in adipocytes did not alter the number of macrophages in adipose tissue, nor did it alter plasma levels of glucose, triglycerides, or fatty acids. We conclude that ZMPSTE24 deficiency in adipocytes, and the accompanying accumulation of farnesyl–prelamin A, reduces adipose tissue stores, but only modestly and only in male mice.

Impact of Progerin Expression on Adipogenesis in Hutchinson—Gilford Progeria Skin-Derived Precursor Cells

“…However, other factors such as poor nutrition and reduced caloric intake could also play a role in the loss of adipose tissue in patients with HGPS and animal models [ 72 ]. Remarkably, Zmpste24 knockout mice, which accumulate unfarnesylated prelamin A, exhibit only a modest reduction in adipose tissue stores in male mice [ 73 ]. This finding supports the notion that farnesylated-prelamin A and progerin impair adipogenesis [ 73 ].…”

“…Remarkably, Zmpste24 knockout mice, which accumulate unfarnesylated prelamin A, exhibit only a modest reduction in adipose tissue stores in male mice [ 73 ]. This finding supports the notion that farnesylated-prelamin A and progerin impair adipogenesis [ 73 ]. Although further in vivo investigations using the HGPS mouse model are needed, we propose that baricitinib treatment could ameliorate or delay the development of generalized lipodystrophy, which is known to affect the metabolism and the appearance of children with HGPS.…”

Abolishing the prelamin A ZMPSTE24 cleavage site leads to progeroid phenotypes with near-normal longevity in mice

“…Zmpste24 −/− mice also have plasma insulin concentrations lower than wild-type mice ( 42 ). Conditional deletion of Zmpste24 from adipocytes leads to only modest body fat loss only in male mice ( 43 ). These findings suggest that decreased body fat in Lmna L648R/L648R mice is not caused by a direct effect of prelamin A on adipocytes.…”

Accelerated aging in articular cartilage by ZMPSTE24 deficiency leads to osteoarthritis with impaired metabolic signaling and epigenetic regulation

“…ZMPSTE24 is a metalloprotease required for the mature of lamin A, which maintains the structural integrity of the nucleus [ 14 – 17 ]. Lamin A is synthesized firstly as a precursor, prelamin A, which terminates in the C-terminal CAAX motif [ 17 ], and prelamin A undergoes four sequential post-translational modifications including isoprenylation of cysteine with a farnesyl lipid moiety, endoproteolytic removal of the -AAX peptide by ZMPSTE24, and carboxyl methylation [ 18 ]. Unlike most other CAAX proteins, prelamin A needs to undergo the second cleavage event to yield mature lamin A, which is also mediated by ZMPSTE24 [ 18 ].…”