**3.2 Type 2 FPLD (FPLD2) and LMNA**

FPLD2 (OMIM #151660) is an autosomal dominant condition that is caused by heterozygous mutations in the *LMNA* gene located on chromosome 1q21–1q22. In contrast to FPLD1 patients who preserve trunk fat, FPLD2 subjects suffer variable and progressive fat loss from the anterior abdomen and chest that occurs after the gradual loss of subcutaneous fat in extremities [6]. Accompanying the loss of

subcutaneous fat is the accumulation of intramuscular (in limbs) and intra-abdominal fat [100]. Despite the similar pattern of fat loss in men and women, women are more prone to develop diabetes, dyslipidemia, and cardiovascular diseases [99].

Most cases of FPLD2 are caused by mutations in the lamin A/lamin C (*LMNA*) gene at the codon position 482 in exon 8 with a variety of mutations, such as p.R482W, p.R482Q, and p.R482L [101, 102]. Subsequently, many more missense mutations in *LMNA* have been reported including p.D230N, p.R399C, p.R439C, p.G465D, p.R471G, p.P485R, p.K486 N, and p.H506D [6, 103, 104]. In the past 3 years, several novel variants of LMNA have been identified such as c.1634G>A (p.R545H) [105], c.1001\_1003delGCC (p.S334del) [106], c.175C>CG (p.L59 V) [107], c.683A>T (p.E228V) [108], c.139G>A (p. D47N) [109], and c.1543A>G (p.K515E) [110]. Notably, mandibuloacral dysplasia type A (MADA), an autosomal recessive disorder, is also caused by homozygous mutations of the *LMNA* gene. Although MADA is a form of lipodystrophy, it is distinctive from FPLD2 [101].

The *LMNA* gene encodes proteins lamin A and lamin C in the nuclear lamina [102]. The lamin proteins have been shown to be able to interact with and affect other regulatory proteins such as chromatin and transcription factors [101]. Therefore, any defects in this structural protein might disrupt the formation and integrity of the nuclear envelope, leading to premature cell death in many tissues, including adipocytes [6, 12]. Recently, lamin A and lamin C have been shown to interact with sterol response element-binding protein 1 (SREBP1), a transcription factor for genes involved in lipid metabolism and adipocyte differentiation [111]. Interestingly, the overexpression of the R482W mutation in primary human preadipocytes and endogenous expression of A-type lamins R482W in fibroblasts of FPLD2 patient fibroblasts impaired the interaction with SREBP1 and thus upregulate many SREBP1target genes [112]. This implies overexpression of SREBP1might lead to the inhibition of adipogenic in FPLD2, which opens a window of SREBP1-targeting therapies against FPLD2 [112].

*Lmna*<sup>−</sup>/<sup>−</sup> mice have been employed to study dilated cardiomyopathy and muscular dystrophy [113]. In both WAT and BAT of *Lmna*<sup>−</sup>/<sup>−</sup> mice, rapamycin inhibits mTORC1 but not mTORC2, leading to the suppression of lipolysis and the restoration of thermogenic uncoupling protein 1 (UCP1) levels, respectively. It indicates that altered mTOR signaling in *Lmna*<sup>−</sup>/<sup>−</sup> mice contributes to lipodystrophic phenotype that can be rescued with rapamycin [113].

Lamin A is maturated from pre-lamin A via multiple-step posttranslational modifications [114]. This process involves a cleavage reaction carried out by an endoplasmic reticulum membrane protease full name ZMPSTE24 located on chromosome 1p34 [115]. Mutations in ZMPSTE24 have been shown to cause mandibuloacral dysplasia type B and autosomal-dominant FPLD2, due to the lack of functional lamin A [116]. Nonetheless, the question as to whether there is an accumulation of pre-lamin A remains controversial. On the one hand, using lamin A/lamin C antibodies and pre-lamin A-specific monoclonal antibodies, one recent study has shown that fibroblasts carrying lipodystrophy-related LMNA mutations (R482W, I299V, C591F, T528 M) do not exhibit an accumulation of pre-lamin A as compared with their WT counterpart [117]. On the other hand, one prior study has demonstrated that the pre-lamin A level is upregulated in *zmpste24*<sup>−</sup>/<sup>−</sup> mice [117].

#### **3.3 Type 3 FPLD (FPLD3) and PPRAG**

FPLD3 (OMIM #151660) is caused by mutations in the *PPRAG* gene on chromosome 3p25. The *PPRAG* gene encodes PPARγ, a nuclear hormone receptor involved in glucose metabolism, adipocyte differentiation, inflammation, and carcinogenesis [118–126]. Importantly, PPARγ is the master transcription factor that governs 60% of genes involved in adipogenesis [127]. Differential RNA splicing along with alternative *Lipodystrophy - A Rare Condition with Serious Metabolic Abnormalities DOI: http://dx.doi.org/10.5772/intechopen.88667*

PPARγ gives rise to different isoforms of PPARγ. While PPARγ 1 and PPARγ3 are ubiquitously expressed in most differentiated cells, PPARγ 2 and PPARγ 4 are strictly found in adipose tissue [126]. PPARγ has three functional domains: a ligand-binding domain (LBD), a DNA-binding domain (DBD), and an A/B domain [126]. Mutations in the PPARγ gene that lead to FLPD have been reported since 1999, mainly in the LBD and DBD [121, 126]. These mutations cause either haploinsufficiency or dysfunction in the normal receptor protein. It has been found that four out of seven mutations in the LBD result in reduced PPARγ activity [118]. For the mutations in the DBD, three out of six cause dysfunction in the wild-type protein [122]. In some cases, loss of function mutations in one of the alleles is also able to induce FLPD3 [126]. A D424N mutation found in two FPLD3 patients in the LBD leads to the downregulation of PPARγ-related transcriptional activity [124]. This loss-of-function effect can be rescued and corrected by the PPARγ agonist rosiglitazone [122]. In fact, treatment with 1 μmol/l or 10 μmol/l of rosiglitazone is able to normalize transcriptional activity of D424N PPARγ [126].

FPLD3 patients with PPARγ-induced FPLD suffer metabolic disorders including hypertriglyceridemia, insulin resistance with raised serum triglyceride and cholesterol levels and raised aminotransferase, and γ-glutamyltranspeptidase activities as well as manifest the symptoms of FPLD including subcutaneous fat loss from the arms, muscular hypertrophy in the legs, and arterial hypertension while having the subcutaneous fat buildup in the face, chin, trunk, and abdomen [128].

### **3.4 Type 4 FPLD (FPLD4) and PLIN1**

It has been reported that null mutations in the *PLIN1* gene causes FPLD4 (OMIM #613877). *PLIN1* encodes perilipin 1 which is found in adipocytes as a LD surface protein [129]. Dysfunction of this protein is likely to cause FPLD4 via in the regulation of LDs and reduced fat mass [130]. However, a latest study using targeted next-generation sequencing of the *PLIN1* gene from 2208 individuals has revealed that haploinsufficiency in *PLIN1* does not result in FPLD [107].

### **3.5 Type 5 FPLD (FPLD5) and CIDEC**

The rare FPLD5 (OMIM #615238) is caused by a homozygous nonsense mutation in the LD protein cell death-inducing Dffa-like effector C (*CIDEC*). The FPLD5 condition is manifested in a 19-year-old Ecuadorian girl with muscular lower limbs and prominent acanthosis nigricans [131]. The mutation induces a premature truncation of the CIDEC protein, and thus it restricts the LD expansion [132]. In fact, *Cidec*<sup>−</sup>/<sup>−</sup> mice have a reduced fat mass and impaired white adipocyte differentiation with multilocular LDs [133]. They are resistant to diet-induced obesity and insulin resistance as seen in the patient [133]. It is deduced from the observations in this study that CIDEC plays an indispensable role in the LD fusion, particularly for the development of unilocular LDs [108].

#### **3.6 Type 6 FPLD (FPLD6) and LIPE**

Exome sequencing has revealed another novel case of FPLD6 (OMIM #615980) that is caused by a homozygous nonsense mutation in the *LIPE* gene on chromosome 19. *LIPE* gene encodes hormone-sensitive lipase (HSL). HSL plays a vital role in lipolysis in which TAG and DAG are hydrolyzed to fatty acids in time of energy need [109]. Patients with FPLD6 have reduced lipolysis, small adipocytes, insulin resistance, and inflammation [134]. In addition, these patients exhibit downregulation of the PPARγ-induced genes in their adipose tissue, which suggests an inhibitory effect on the regulation of adipogenesis. Two FPLD6 patients from Italy have

been reported to have mild muscular dystrophy with an increased serum creatine kinase level as well as other metabolic features such as dyslipidemia and diabetes [135]. In rodents, HSL also plays an important role in reproduction, specifically in male testes where it participates in steroid hormone synthesis from cholesterol [136]. In fact, *Lipe*<sup>−</sup>/<sup>−</sup> mice manifest impaired spermatogenesis, azoospermia, and male infertility [136].
