Energy balance in congenital generalized lipodystrophy type I

Abstract

Congenital generalized lipodystrophy type 1 (CGL-1) is characterized by an absence of adipose tissue and decreased serum leptin levels. Low leptin levels in CGL-1 support the claim that subjects are hypermetabolic and hyperphagic. The present study examines this claim. We determined 24-hour energy expenditure (24-h EE) (kilocalories) (n = 2) and resting metabolic rate (RMR) per kilogram of lean body mass (LBM) (n = 3) in CGL-1 and in 18 healthy control subjects. The 24-h EEs of control and subjects with CGL were compared with respect to kilocalories required per day relative to kilograms of LBM and with respect to RMR relative to kilograms of LBM. Fasting leptin, adiponectin, and 24-hour ghrelin levels were also measured in subjects with CGL-1. The 24-h EE per kilogram of LBM for the subjects with CGL-1 falls on the same regression line observed for this relationship in the controls. The RMR per kilogram of LBM in subjects with CGL-1 also was similar to that in controls. Both 24-h EE and RMR were quite increased when reported per kilogram of total body weight. Subjects with CGL-1 also have decreased fasting leptin and adiponectin hormone levels and no premeal ghrelin rise. People with CGL-1 have similar RMR and daily caloric requirements as healthy controls when these parameters are expressed as a function of LBM. Appetite-regulating hormone levels in CGL-1 suggest that multiple factors act to control appetite in these individuals.

Introduction

Congenital generalized lipodystrophy (CGL) is an autosomal recessive disorder characterized by the absence of adipose tissue and leptin deficiency. Berardinelli [1] first described CGL in 1954 in 2 children with hepatomegaly, marked muscular development, and milky serum. In 1968, we [2] reported a variant form of CGL in an African American family with a similar phenotype that, in addition, featured cystic bone lesions. More than 30 years later, the CGL variant associated with bone disease was classified as CGL type 1 (CGL-1), resulting from mutations in the gene for AGPAT2 (1-acylglycerol-3-phosphate O-acyltransferase 2), located at 9q34 [3], [4], [5]. AGPAT2, also known as LPAATβ gene (lysophosphatidic acid acyltransferase β), catalyzes the formation of phosphatidic acid, a critical component of phospholipids and triglyceride synthesis. The CGL variant initially described by Berardinelli [1] and later by Seip [6] is consistent with characteristics seen in CGL type 2 (CGL-2). Congenital generalized lipodystrophy type 2 results from mutations in the gene for seipin (at 11q13) that encodes an integral membrane protein of the endoplasmic reticulum [7], [8].

Both CGL variants have been reported to be associated with increased energy intake and increased resting metabolic rate (RMR) with respect to total body weight (TBW) [9]. The metabolic demands of individuals with congenital leptin deficiency [10] are consistent with the continuous pattern of food intake [1], [11], [12], [13], [14], [15], [16] and low serum leptin levels reported in people with CGL [17]. Energy requirements are predominantly determined by lean body mass (LBM) because triglyceride stores in adipose tissue are metabolically inactive. Because adipose tissue is effectively absent in CGL, LBM accounts for a higher proportion of the TBW in these individuals. Therefore, energy expenditure in CGL reported as a function of TBW [9] may have been previously overestimated. To determine energy requirements in CGL-1, we compared the daily caloric intake and RMR (as a function of LBM) in CGL-1 and healthy control subjects.