Seipin Deficiency as a Model of Severe Adipocyte Dysfunction: Lessons from Rodent Models and Teaching for Human Disease

Abstract

Obesity prevalence is increasing worldwide, leading to cardiometabolic morbidities. Adipocyte dysfunction, impairing white adipose tissue (WAT) expandability and metabolic flexibility, is central in the development of obesity-related metabolic complications. Rare syndromes of lipodystrophy characterized by an extreme paucity of functional adipose tissue should be considered as primary adipocyte dysfunction diseases. Berardinelli-Seip congenital lipodystrophy (BSCL) is the most severe form with a near absence of WAT associated with cardiometabolic complications such as insulin resistance, liver steatosis, dyslipidemia, and cardiomyopathy. Twenty years ago, mutations in the BSCL2 gene have been identified as the cause of BSCL in human. BSCL2 encodes seipin, an endoplasmic reticulum (ER) anchored protein whose function was unknown back then. Studies of seipin knockout mice or rats demonstrated how seipin deficiency leads to severe lipodystrophy and to cardiometabolic complications. At the cellular levels, seipin is organized in multimers that are particularly enriched at ER/lipid droplet and ER/mitochondria contact sites. Seipin deficiency impairs both adipocyte differentiation and mature adipocyte maintenance. Experiments using adipose tissue transplantation in seipin knockout mice and tissue-specific deletion of seipin have provided a large body of evidence that liver steatosis, cardiomyopathy, and renal injury, classical diabetic complications, are all consequences of lipodystrophy. Rare adipocyte dysfunctions such as in BSCL are the key paradigm to unravel the pathways that control adipocyte homeostasis. The knowledge gathered through the study of these pathologies may bring new strategies to maintain and improve adipose tissue expandability.

Role of Seipin in Human Diseases and Experimental Animal Models

“…(6) Seipin deficiency accelerates lipolysis. This phenomenon is only observed during the early stage of seipin loss because there are rare TAGs left after this period [ 43 , 45 , 46 ]. Elevated adipose triglyceride lipase (ATGL) stability and expression, increased phosphorylation of hormone-sensitive lipase (HSL) and perilipin 1 (PLIN1) contribute to seipin deficiency-induced lipolysis acceleration [ 47 , 48 ].…”

“…Strikingly, the expression of SEIPIN in the brain is inversely correlated with age, but strongly and positively associated with anti-oxidative stress enzymes such as (superoxide dismutase 1 and 2 and PPARγ) [ 57 ]. Therefore, the mutations of BSCL2 usually induce a variety of serious clinical consequences ( Figure 1 , Table 1 and Supplementary Table S1 ), including CGL2 (OMIM #269700; highest prevalence, estimated to be 0.1–5 persons per million [ 45 , 58 ]), PELD (OMIM #615924; only nine patients reported worldwide so far) [ 59 ], and BSCL2 -associated motor neuron diseases (OMIM #619112 or OMIM #270685; secondary prevalence).…”

“…Metabolic disorders are the predominant characteristics of SKO mice and attract numerous researchers investigating the underlying mechanisms and potential therapeutic targets ( Table 4 ). Magré and Prieur have elegantly summarised the phenotypes and underlying mechanisms of metabolic disorders and the complications of CGL2 in mice in a recent review [ 45 ]. Therefore, rather than replicating their findings, this review complements this by adding some other findings that are not mentioned in their review.…”

“…In the review, Magré and Prieur described that seipin deficiency causes severe lipodystrophy by impairing adipogenesis, accelerating lipolysis, damaging LD homeostasis and other unclear mechanisms [ 45 ]. Here, we want to discuss whether the metabolic disturbance is caused by adipose tissue loss in SKO mice.…”

“…(3) Seipin contributes to normal cardiac function. It is well known that SKO mice develop hypertrophic cardiomyopathy with diastolic dysfunction [ 45 ]. Researchers have studied the underlying mechanisms of it in SKO mice and in cardiomyocyte-specific seipin knockout (seipin-cKO) mice.…”