Congenital generalized lipodystrophies—new insights into metabolic dysfunction

Abstract

Congenital generalized lipodystrophy (CGL) is a heterogeneous autosomal recessive disorder characterized by a near complete lack of adipose tissue from birth and, later in life, the development of metabolic complications, such as diabetes mellitus, hypertriglyceridaemia and hepatic steatosis. Four distinct subtypes of CGL exist: type 1 is associated with AGPAT2 mutations; type 2 is associated with BSCL2 mutations; type 3 is associated with CAV1 mutations; and type 4 is associated with PTRF mutations. The products of these genes have crucial roles in phospholipid and triglyceride synthesis, as well as in the formation of lipid droplets and caveolae within adipocytes. The predominant cause of metabolic complications in CGL is excess triglyceride accumulation in the liver and skeletal muscle owing to the inability to store triglycerides in adipose tissue. Profound hypoleptinaemia further exacerbates metabolic derangements by inducing a voracious appetite. Patients require psychological support, a low-fat diet, increased physical activity and cosmetic surgery. Aside from conventional therapy for hyperlipidaemia and diabetes mellitus, metreleptin replacement therapy can dramatically improve metabolic complications in patients with CGL. In this Review, we discuss the molecular genetic basis of CGL, the pathogenesis of the disease's metabolic complications and therapeutic options for patients with CGL.

The role of leptin in diabetes: metabolic effects

“…In support of this, rodent models of leptin deficiency are characterised by insulin resistance and diabetes [8,9], and leptin treatment lowers blood glucose and insulin levels [10] independent of changes in food intake and body weight [11]. Moreover, leptin administration in both rodents [12,13] and humans [14] ameliorates the severe insulin resistance and diabetes phenotype characteristic of other models of leptin deficiency that are not associated with obesity, such as lipodystrophy, a condition characterised by loss of adipose tissue owing to mutations that impair adipogenesis [15]. Taken together, these data suggest that leptin regulates glycaemic control in addition to energy balance in both rodent models and clinical settings.…”

Hepatic Lipodystrophy in Galloway Calves

“…7,26,45,46 Familial hyperlipoproteinemia in cats, 47 idiopathic hyperlipoproteinemia in dogs, 41 and congenital generalized lipodystrophies in humans 32 have been identified to be inherited defects in lipid metabolism. In the present case, all affected calves were the progeny of 1 bull that had been introduced into the herd in 2010 and was slaughtered in 2013.…”

Dunnigan-Type Familial Partial Lipodystrophy: Understanding and Treating the Syndrome

“…The suggested recombinant leptin dose is based on the patient's body weight (Table 4). Aesthetic treatments for FPLD2 include facial filling, autologous adipose tissue transplant, and reconstructive surgeries such as liposuction, with the possibility of recurrence of abnormal adipose tissue deposition in areas where liposuction is performed [35] [36]. Dermatological treatment is suggested for skin bleaching caused by acanthosis, along with hair removal using definitive depilation.…”