Advertisement

Diabetologia

, Volume 48, Issue 12, pp 2641–2649 | Cite as

Adipokines and the insulin resistance syndrome in familial partial lipodystrophy caused by a mutation in lamin A/C

  • S. P. Y. Wong
  • M. Huda
  • P. English
  • A. Bargiotta
  • J. P. H. Wilding
  • A. Johnson
  • R. Corrall
  • J. H. PinkneyEmail author
Article

Abstract

Aims/hypothesis

Familial partial lipodystrophy (FPLD) and obesity are both associated with increased risks of type 2 diabetes and cardiovascular disease. Although adipokines have been implicated, few data exist in subjects with FPLD; therefore we investigated a family with FPLD due to a lamin A/C mutation in order to determine how abnormalities of the plasma adipokine profile relate to insulin resistance and the metabolic syndrome.

Methods

Plasma levels of adiponectin, leptin, resistin, IL-1β, IL-6 and TNF-α in 30 subjects (ten patients, 20 controls) were correlated with indices of metabolic syndrome.

Results

Compared with controls, FPLD patients had significantly lower plasma levels of adiponectin (3.7±1.0 in FDLP cases vs 7.1±0.72 μg/ml in controls, p=0.02), leptin (1.23±0.4 vs 9.0±1.3 ng/ml, p=0.002) and IL-6 (0.59±0.12 vs 1.04±0.17 pg/ml, p=0.047) and elevated TNF-α (34.8±8.1 vs 13.7±2.7 pg/ml, p=0.028), whereas IL-1β and resistin were unchanged. In both groups, adiponectin levels were inversely correlated with body fat mass (controls, r=−0.44, p=0.036; FDLP, r=−0.67, p=0.025), insulin resistance (controls, r=−0.62, p=0.003; FDLP, r=−0.70, p=0.025) and other features of the metabolic syndrome. TNF-α concentrations were positively related to fat mass (controls, r=0.68, p=0.001; FDLP, r=0.64, p=0.048) and insulin resistance (controls, r=0.86, p=0.001; FDLP, r=0.75, p=0.013). IL-6, IL-1β and resistin did not demonstrate any correlations with the metabolic syndrome in either group.

Conclusions/interpretation

Low adiponectin and leptin and high TNF-α were identified as the major plasma adipokine abnormalities in FPLD, consistent with the hypothesis that low adiponectin and high TNF-α production may be mechanistically related, and perhaps responsible for the development of insulin resistance and cardiovascular disease in FPLD.

Keywords

Adipokines Adiponectin Diabetes Insulin resistance Lipodystrophy Obesity TNF-α 

Abbreviations

FPLD

familial partial lipodystrophy

HIV

human immunodeficiency virus

HOMA-IR

homeostasis model assessment of insulin resistance

IQR

interquartile range

Introduction

Familial partial lipodystrophy (FPLD) of the Dunnigan variety is an autosomal dominant form of insulin resistance caused by a mutation of the lamin A/C (LMNA) gene, which encodes a component of the nuclear envelope [1]. Affected subjects have a normal phenotype at birth but develop gradual redistribution of adipose tissue after the onset of puberty, with loss of subcutaneous adipose tissue in the extremities and gluteal region and accumulation of increased cervicofacial and intra-abdominal visceral adipose tissue and intramyocellular lipid [1]. Despite an overall reduction in body fat, individuals with FPLD paradoxically demonstrate features of the metabolic syndrome typically seen in obesity, including insulin resistance, hyperinsulinaemia, type 2 diabetes, dyslipidaemia, and increased serum C-reactive protein and NEFA levels [2], leading to premature cardiovascular disease [1, 3]. The mechanisms underlying the pathogenesis of the metabolic phenotype in FPLD remain uncertain; however, it is possible either that the absolute loss and redistribution of adipose tissue, or intrinsic dysfunction of adipose tissue itself arising directly from the genetic defect, could lead to the development of the metabolic abnormalities.

It is now recognised that adipose tissue, besides its role as a depot for energy storage, is also an active endocrine organ, enhancing the effects of a large number of factors and hormones with important effects on fuel metabolism and inflammation [4]. Abnormalities in the production of these adipose tissue-derived products, collectively termed ‘adipokines’, have been postulated to play major roles in the pathogenesis of the metabolic syndrome related to obesity [4]. Among the adipokines secreted by adipose tissue are TNF-α, IL-6, IL-1β and the more recently described hormones adiponectin and resistin. In view of the paradoxical occurrence of the metabolic syndrome in individuals with depleted adipose tissue, FPLD is an interesting experiment of nature that may shed important light on how abnormalities of adipose tissue lead to metabolic disease. Recently, adiponectin levels were found to be reduced in patients with acquired and congenital lipodystrophies [2, 5] and there was a strong negative correlation between adiponectin and fasting insulin concentrations [5]. Moreover, the administration of adiponectin partially corrected the insulin resistance of lipoatrophic mice [6], suggesting that hypoadiponectinaemia may be an important mediator of insulin resistance in lipodystrophy. Thus, the low-adiponectin state may be the common defect in both obesity and lipodystrophy. However, increased plasma levels of various proinflammatory cytokines expressed by adipose tissue have also been observed in various groups of lipodystrophic subjects [7, 8, 9, 10, 11]. The aim of the present study was to investigate the interrelationships between the abnormalities of adiponectin and other adipokines, and to determine which defects are most closely predictive of the metabolic syndrome in a genetically and phenotypically well-characterised group of subjects with FPLD and unaffected controls.

Subjects and methods

Subjects

We studied ten patients from a single family with a history of FPLD. The ten patients were previously demonstrated to have a mutation (R482Q) in the LMNA gene [12, 13]. These subjects were matched for age, sex and BMI with four unaffected control subjects from the same family, but without the LMNA mutation. We also studied and included as additional controls 16 matched healthy volunteers with no family history of FPLD. Three of the FPLD group and four of the control group had type 2 diabetes, treated either with diet or with diet in combination with oral hypoglycaemic agents. The diagnosis of type 2 diabetes was made on the known clinical history and a fasting glucose of more than 7.0 mmol/l. The history of vascular disease was obtained from previous clinical accounts of cardiovascular or cerebrovascular ischaemic events. The use of antihypertensive and lipid-lowering drugs was also recorded. Subjects were asked to fast, drink only water and avoid smoking from 2200 hours on the night before the study, and refrain from strenuous physical exercise or alcohol in the 24 h prior to the study day. All subjects gave written informed consent. The study was approved by the local Research Ethics Committee and performed in accordance with the principles of the Declaration of Helsinki.

Measurements

BMI, waist and hip circumference were measured and the WHR was then calculated. Blood pressure was measured in the supine position from the right arm using an Omron HEM-705C (Omron International, Kyoto, Japan). The mean of three separate readings taken at 3-min intervals was used in the analysis. Body composition was assessed by whole-body electrical bioimpedance analysis (Bodystat 1500, Isle of Man, UK), allowing the measurements of total fat mass and percentage body fat. Blood samples were taken into plastic EDTA tubes and immediately separated by centrifugation at 4°C. Plasma samples were stored at −70°C until analysis.

Assay methods

Plasma glucose concentrations were measured in duplicate by the glucose hexokinase method using the Advia 1650 system (Bayer UK, Newbury, UK). Total cholesterol, HDL-cholesterol, directly obtained LDL-cholesterol and triglyceride levels were assayed by the routine biochemistry laboratory at Southmead Hospital, Bristol. Fasting plasma insulin was determined by an ELISA (BioSource Europe, Nivelles, Belgium), with a sensitivity of 0.15 IU/ml and intra-assay CV of 6.0%. Insulin resistance was estimated using the homeostasis model of insulin resistance (HOMA-IR) with the following formula: HOMA-IR=fasting insulin (IU/ml)×fasting glucose (mmol/l)/22.5 [14]. Plasma adiponectin was measured using an ELISA (B-Bridge International, supplied by Metachem Diagnostics, Northampton, UK) with a detection limit of 0.25 ng/ml and intra-assay CV of 4.1%. Plasma resistin levels were determined by an ELISA (BioVendor Medical Laboratory, Brno, Czech Republic) with a detection limit of 0.5 ng/ml and a mean intra-assay CV of 5.7%. Leptin was measured by ELISA (BioSource Europe), with a minimal detection limit of 1 ng/ml and an intra-assay CV of 4.9%. TNF-α and IL-1β were determined using ELISA (IBL, Hamburg, Germany) with detection limits of 0.6 pg/ml and intra-assay CV between 3.5 and 6.0%. IL-6 concentrations were measured using an ELISA (HS Quantikine; R&D Systems Europe, Abingdon, UK) with a minimal detection limit of 0.05 pg/ml and CV between 2.1 and 8.4%.

Statistical analysis

The Statistical Package for the Social Sciences version 11.5 (SPSS, Chicago, IL, USA) was used for data analysis. The distributions of the variables were tested for normality using the Shapiro–Wilk W test. Summary statistics are presented as mean±SEM. Because of small numbers in the group with a family history of FPLD (but without the LMNA mutation), these subjects were pooled with other unaffected controls for analysis. Comparisons between groups were made using two-tailed Student’s t test or the Mann–Whitney U test as appropriate. Categorical variables were compared using Fisher’s exact test. Plasma adipokine levels are illustrated as box plots showing the interquartile range (IQR) and range. The concentrations of the adipokines and HOMA-IR were positively skewed and were log-transformed to a normal distribution to calculate Pearson (r) correlation coefficients, in order to explore the relations between plasma adipokine concentrations and demographic and metabolic characteristics. Standardised regression coefficients (β) were calculated to determine associations between variables. Significance was defined at p<0.05.

Results

Demographic and clinical comparisons

Demographic and clinical characteristics for all subjects are shown in Table 1. The two groups were of similar age and sex. Despite similar BMI and WHR, FPLD patients had lower body fat content but higher prevalences of type 2 diabetes and cardiovascular disease. Although diastolic blood pressure and the use of antihypertensive therapy were not significantly different between the two groups, systolic blood pressure was higher in subjects with FPLD. Additionally, despite greater usage of lipid-lowering drugs in FPLD subjects, they had significantly higher serum total cholesterol and triglyceride levels and lower HDL-cholesterol levels than control subjects.
Table 1

Biochemical and anthropomorphic characteristics of FPLD and control subjects

 

FPLD

Controls

p (difference)

Number

10

20

 

Age (years)

38.9±6.28

44.5±3.08

NS

Sex (male/female)

3/10

6/20

 

Diabetes (%)

30

20

NS

Vascular disease (%)

50

10

0.019

BMI (kg/m2)

23.1±1.47

25.1±1.23

NS

WHR

0.854±0.01

0.85±0.024

NS

Fat mass (kg)

12.8±2.1

22.0±2.6

0.014

Body fat (%)

19.72±2.1

31.3±2.1

0.0024

Total cholesterol (nmol/l)

6.60±0.35

5.41±0.24

0.024

HDL-cholesterol (mmol/l)

1.12±0.11

1.63±0.08

0.004

LDL-cholesterol (mmol/l)

4±0.4

3.17±0.23

NS

Dyslipidaemia treatment

40%

0%

0.008

Fasting triglycerides (nmol/l)

4.8±1.9

1.16±0.13

0.001

Systolic BP (mmHg)

147.3±9.76

122.39±4.66

0.015

Diastolic BP (mmHg)

79.5±4.53

77.62±3.0

NS

Hypertension treatment (%)

30

10

NS

Fasting insulin (U/l)

10.93±2.89

5.86±0.78

0.030

HOMA-IR

3.1±0.6

1.6±0.3

0.016

Fasting glucose (mmol/l)

5.49±0.34

5.73±0.53

NS

NS not significant

Values are mean±SEM

Significance is defined as p<0.05

Adipokines

Mean leptin and adiponectin levels were significantly lower in FPLD than in control subjects (Table 2, Fig. 1a, b). Furthermore, diabetic subjects in both groups demonstrated lower levels of adiponectin compared with non-diabetic subjects for FPLD and controls, respectively. In contrast, resistin concentrations in the two groups did not differ (Table 2, Fig. 1c). Plasma TNF-α, but not IL-1β, was significantly elevated in FPLD compared with control subjects (Table 2, Fig. 1d, e), whereas levels of IL-6 were reduced in affected subjects (Table 2, Fig. 1f).
Table 2

Plasma concentrations of adipokines in FPLD and control subjects

 

FPLD

Controls

p (difference)

Adiponectin (μg/ml)

3.7±1.0

7.1±0.72

0.02

Leptin (ng/ml)

3.0±0.4

9.0±1.3

0.002

Resistin (ng/ml)

27.6±2.4

30.7±4.1

NS

TNF-α (pg/ml)

34.8±8.1

13.7±2.7

0.028

IL-6 (pg/ml)

0.59±0.12

1.04±0.17

0.047

IL-1β (pg/ml)

1.45±0.26

1.77±0.23

NS

NS not significant

Values are mean±SEM

Significance is defined as p<0.05

Fig. 1

Box plots illustrating plasma levels of (a) adiponectin, (b) resistin, (c) leptin, (d) TNF-α, (e) IL-6 and (f) IL-1β in FPLD and control subjects. Boxes represent median and interquartile ranges. Error bars represent 10th and 90th percentiles. Significance is defined as *p<0.05. NS not significant

Univariate correlations

The principal factors affecting adipokine concentrations were explored by linear regression analysis in controls and FPLD subjects separately (Table 3). In control subjects, plasma adiponectin levels correlated inversely with fat mass (Fig. 2a), BMI, WHR, triglycerides, fasting glucose and insulin, HOMA-IR (Fig. 2b) and TNF-α concentrations (Fig. 2c), whereas there was a positive correlation with HDL-cholesterol concentrations. Furthermore, the levels of plasma TNF-α were strongly related to increasing fat mass, BMI, body fat percentage, HOMA-IR, plasma insulin and glucose, but not to WHR. In subjects with FPLD, plasma adiponectin also correlated inversely with fat mass (Fig. 2b), BMI, fasting insulin and glucose, HOMA-IR (Fig. 2a), triglycerides and plasma TNF-α (Fig. 2c), and HDL-cholesterol was also positively associated with adiponectin concentrations. TNF-α concentrations also positively correlated with fat mass and BMI, as well as HOMA-IR and fasting insulin levels.
Table 3

Correlation analyses of adipokine concentrations with metabolic and obesity-related indices

 

Adiponectin

TNF-α

IL-6

FPLD

Controls

FPLD

Controls

FPLD

Controls

r

p

r

p

r

p

r

p

r

p

r

p

BMI

−0.72

0.019

−0.51

0.022

0.70

0.007

0.62

0.004

0.60

0.046

0.54

0.013

WHR

0.012

NS

−0.45

0.046

0.12

NS

0.22

NS

0.15

NS

0.41

0.019

Fat mass

−0.67

0.025

−0.44

0.036

0.64

0.048

0.68

0.001

0.74

0.014

0.58

0.007

Body fat (%)

−0.316

0.037

−0.26

0.028

0.37

NS

0.49

0.028

0.75

0.013

0.45

0.01

Total cholesterol

0.15

NS

0.03

NS

0.10

NS

0.05

NS

0.21

NS

0.09

NS

HDL-cholesterol

0.72

0.018

0.52

0.019

−0.54

NS

−0.4

NS

−0.475

NS

−0.38

NS

LDL-cholesterol

−0.09

NS

−0.09

NS

−0.05

NS

0.22

NS

0.02

NS

0.15

NS

Triglycerides

−0.61

0.016

−0.49

0.029

0.49

NS

0.37

NS

0.26

NS

0.3

NS

Systolic BP

−0.12

NS

−0.1

NS

0.50

NS

0.1

NS

0.39

NS

0.19

NS

Diastolic BP

−0.07

NS

−0.19

NS

0.39

NS

0.23

NS

−0.27

NS

0.28

NS

Fasting insulin

−0.78

0.009

−0.58

0.008

0.79

0.006

0.8

0.001

0.52

NS

0.57

0.009

Fasting glucose

−0.52

0.02

−0.53

0.015

0.56

NS

0.65

0.001

0.43

NS

0.62

0.003

HOMA-IR

−0.70

0.025

−0.62

0.003

0.75

0.013

0.86

0.001

0.59

NS

0.64

0.003

Adiponectin

−0.78

0.008

−0.53

0.017

−0.28

NS

−0.37

0.037

Leptin

−0.45

NS

−0.46

0.044

0.45

NS

0.66

0.001

0.71

0.001

0.49

0.025

TNF-α

−0.78

0.008

−0.53

0.017

0.37

NS

0.53

0.016

IL-6

−0.28

NS

−0.37

0.037

0.37

NS

0.53

0.016

IL-1β

−0.21

NS

−0.1

NS

0.06

NS

0.1

NS

−0.03

NS

−0.1

NS

Resistin

0.13

NS

−0.04

NS

0.08

NS

0.16

NS

0.36

NS

0.24

NS

NS not significant

Relationships between various adipokines were also explored and are shown at the bottom of the table

Significance is defined as p<0.05

Fig. 2

Relationships between plasma adiponectin and (a) HOMA-IR, (b) fat mass and (c) plasma TNF-α levels in FPLD and unaffected subjects. Circles, controls; squares, FPLD. HOMA-IR, fat mass and plasma TNF-α were log-transformed to normalise distribution. Significance is defined as p<0.05

In the control group, as expected, plasma leptin levels correlated positively with BMI, WHR, fat mass, body fat percentage, fasting insulin and glucose, HOMA-IR, TNF-α and IL-6 (Table 3). In FPLD subjects, leptin concentrations positively correlated with BMI, fat mass and body fat percentage. However, plasma leptin and TNF-α concentrations were not correlated significantly (r=0.45, p=0.10), in contrast with control subjects (r=0.66, p=0.001).

In both groups, plasma IL-6 levels positively correlated with BMI, fat mass and body fat percentage as well as plasma leptin concentrations (Table 3). In control subjects, there were strong positive correlations between plasma IL-6 levels and HOMA-IR, fasting insulin and glucose. Moreover, plasma IL-6 was inversely related to adiponectin levels. In contrast, these relationships were not observed in the FPLD group. Similarly, although there was a significant positive correlation between IL-6 and TNF-α in the control group, this was not observed in FPLD. We were unable also to demonstrate any relationships between plasma IL-1β and any of the anthropometric or metabolic variables in either group of subjects. Plasma resistin levels also showed little or no relationship with these variables, with the exception that plasma resistin levels showed weak positive correlations with total cholesterol (r=0.64, p=0.047) and triglycerides (r=0.73, p=0.016) and a weak negative correlation with HDL-cholesterol (r=−0.61, p=0.049) in the FPLD group alone.

Multivariate analysis

Using multivariate regression analysis, HOMA-IR was inversely related with adiponectin levels in control subjects, after controlling for measures of obesity, including fat mass, BMI and WHR (β=−0.62, p=0.047). There was also a positive correlation between HDL-cholesterol and adiponectin concentrations, but this did not reach significance after controlling for the above measures of obesity (β=0.41, p=0.061). Subjects with FPLD demonstrated similar findings, whereby HOMA-IR was again related to adiponectin concentrations after correction for fat mass and BMI (β=−0.92, p=0.046). As with the control group, there was a trend towards positive correlation between HDL-cholesterol and adiponectin concentrations after adjusting for obesity-related variables (β=0.54, p=0.11).

In control subjects, using similar multiple regression models with adjustment for fat mass, BMI and HOMA-IR, neither plasma TNF-α nor IL-6 concentration correlated with adiponectin levels. However, in FPLD subjects TNF-α was independently related to plasma adiponectin concentrations after adjusting for BMI and fat mass and HOMA-IR (β=−0.91, p=0.02).

Discussion

This study shows that FPLD is characterised by marked abnormalities in the adipokine profile, principally reduced circulating levels of adiponectin and leptin and increased levels of TNF-α, but with little change in concentrations of several other adipokines, including IL-6, resistin and IL-1β. These abnormalities were closely related to insulin resistance and the metabolic syndrome. We also show that plasma adiponectin levels were inversely related to indices of insulin resistance and obesity, in agreement with previous work [5, 15, 16]. Both increased TNF-α and reduced adiponectin levels have been implicated in the pathogenesis of the metabolic syndrome [17, 18, 19, 20] and may therefore contribute to the development of this syndrome in FPLD. In this respect, subjects with FPLD behave as if they were obese, even though they are deficient in adipose tissue.

Adiponectin is expressed exclusively by adipocytes and, in contrast to other adipokines, plasma levels decline with increasing adiposity [16, 21, 22] and increase with weight loss [21, 23]. Recent work suggests that adiponectin levels are influenced more by intra-abdominal (visceral) than by subcutaneous adipose tissue [22, 24], and that plasma levels correlate with insulin sensitivity [16, 25, 26]. Low adiponectin levels are also associated with type 2 diabetes [15, 27], dyslipidaemia [28] and cardiovascular disease [29]. The best evidence that adiponectin deficiency plays a causal role in the pathogenesis of insulin resistance is from lipoatrophic mice with low levels of adiponectin. In this model, insulin resistance was partially ameliorated by administration of adiponectin [6]. Thus, the present data support the proposition that adiponectin deficiency contributes to the pathogenesis of insulin resistance in human FPLD.

There have been relatively few studies examining other proinflammatory cytokines in human lipodystrophies. TNF-α is of particular interest, having been closely linked to obesity and the metabolic syndrome [20]. In contrast to our data, Hegele et al. [2] found no change in plasma TNF-α in FPLD, although a recent case report of an individual with acquired idiopathic generalised lipodystrophy reported elevated plasma TNF-α in the presence of reduced adiponectin and leptin levels [10]. The relationship between adiponectin and the TNF-α system is of particular interest. TNF-α suppresses adiponectin gene expression in cultured human and rodent adipocytes [19, 30, 31, 32] and plasma levels of adiponectin are inversely related to plasma TNF-α and adipocyte TNF-α gene expression [7, 17, 33]. Furthermore, adiponectin knockout mice exhibit increased levels of TNF-α in adipose tissue and plasma [34]. Conversely, adiponectin inhibits TNF-α production in cultured macrophages [35] and myotubes [34]. Animal models of lipodystrophy also exhibit upregulation of TNF-α. Thus, mice transgenic for aP2-SREPB (adipocyte specific enhancer/promoter-sterol regulatory element-binding protein 1c) demonstrated elevated expression of TNF-α in adipose tissue [36, 37], and conjugated linoleic acid supplementation elicits a lipodystrophic phenotype with enhanced TNF-α expression in adipocytes [38]. Furthermore, a recent study demonstrated increased subcutaneous adipose tissue TNF-α expression in HIV-related lipodystrophy concomitantly with reduced adiponectin levels [11]. Thus, the present observation of a strong inverse relationship between adiponectin and TNF-α is consistent with the idea that TNF-α and adiponectin are reciprocally related, and that this relationship may result directly from reciprocal regulatory effects of TNF-α and adiponectin on adipocytes, and of adiponectin on macrophage TNF-α expression. It is interesting to speculate that FPLD somehow leads to amplification of this reciprocal relationship, with harmful consequences for insulin resistance. It is currently unclear whether the increased TNF-α production in FPLD comes from visceral adipose tissue, macrophages or other tissues. It is possible that abnormal redistribution of fat in FPLD, rather than the absolute degree of adiposity, may account for the elevated levels of TNF-α. Circulating levels of adiponectin also appear to be more closely related to visceral adiposity [22, 39], although large lipid-rich visceral adipocytes also appear to produce less adiponectin [39]. Thus, although FPLD leads to expanded visceral adipose tissue depots [40], it is possible to speculate that this does not compensate for the loss of peripheral subcutaneous adipose tissue, and that overall systemic adiponectin production falls.

In contrast to TNF-α, levels of IL-6 were lower in FPLD subjects than in control subjects (0.59 vs 1.04 pg/ml, p=0.047). A possible explanation is that adipose tissue is a major site of IL-6 production, accounting for up to 35% of circulating levels [41]; the reduced IL-6 concentrations in FPLD may reflect reduced total fat mass. Consistent with previous work, however, IL-6 levels were positively related to indices of obesity and insulin resistance [42] and inversely with adiponectin levels in the control group [19, 42, 43]. By contrast, in FPLD, although there was a correlation with obesity-related indices, we failed to find strong relationships of IL-6 with metabolic indices, although this was probably influenced by the small sample size. However, although IL-6 and TNF-α are both proinflammatory cytokines, plasma levels of IL-6 in this situation may be a marker of fat mass rather than being directly related to the metabolic syndrome in a mechanistic fashion [44]. In support of this, the study by Vozarova [45] demonstrated that although IL-6 was positively related to insulin resistance and fat mass, there was no correlation between IL-6 and insulin action, after adjustment for adiposity. A recent study also found that although there was no relationship between insulin sensitivity, as measured by hyperinsulinaemic–euglycaemic clamp and plasma IL-6 levels, there was a very strong correlation between IL-6 and BMI [46]. While our findings are in accordance with previous studies [19, 42, 43], it is possible that plasma IL-6 levels may be a reflection of fat mass rather than a mediator of insulin resistance.

We also failed to observe any change in plasma IL-1β in FPLD, or relationships with other metabolic variables. IL-1β is an important immune cytokine released by a large variety of cells, including adipocytes [47], in which it may have a paracrine effect. IL-1β has been shown to inhibit adipocyte maturation and lipid accumulation [48] and to suppress expression of adiponectin [49] and leptin [50]. Thus, although the present data do not exclude significant autocrine/paracrine interactions of IL-6 and IL-1β in the regulation of adiponectin and TNF-α production within adipose tissue, from these data at least the former of the two adipokines appears less likely to be important circulating mediators of the metabolic syndrome. Likewise, plasma resistin levels were similar in both FPLD and control subjects and there were no demonstrable relationships with any of the anthropometric variables or indices of the metabolic syndrome. However, resistin levels were found to be positively related to total cholesterol and triglyceride levels and negatively to HDL-cholesterol in the FPLD group only. Resistin is an adipokine that has been proposed to be an important link between insulin-resistant states and obesity. Circulating levels of resistin are elevated in diet-induced and genetic forms of obesity in mice (ob/ob and db/db) and are reduced in response to insulin-sensitising thiazolidinediones [51]. A recent study demonstrated that resistin knockout mice exhibit lowered hepatic glucose output and improved fasting glycaemia [52]. However, reports of resistin in humans remain more controversial [53]. Thus, although some studies demonstrate that circulating resistin [54] or resistin gene polymorphism [55] have significant positive relationships with obesity and insulin resistance, in others findings have been discordant [56]. Despite the lack of correlation of resistin with most of the anthropometric and metabolic variables, in the FPLD group, those with total and HDL-cholesterol as well as triglycerides were significant. However, the majority of the present findings suggest that resistin plays a less important role than adiponectin and TNF-α in the metabolic syndrome, which may be related to species differences in the influence of resistin on metabolic processes [53].

Finally, it is important to note that this was a cross-sectional study which was quite clearly limited by the small numbers of subjects studied. Additional studies with a more substantial number of subjects and, if possible, interventional experiments would be required to confirm the relationships proposed here and to determine cause-and-effect relationships.

In conclusion, this study has shown that FPLD is a state of low adiponectin and raised TNF-α production, and that these abnormalities are closely and inversely related to each other and to the metabolic syndrome. In contrast, little or no relationship was observed between metabolic parameters and circulating levels of IL-6, IL-1β or resistin. Adiponectin and TNF-α may play direct roles in the pathogenesis of cardiovascular disease and diabetes in FPLD.

Notes

Acknowledgement

This work was funded by the University of Liverpool Research Development Fund.

References

  1. 1.
    Garg A (2004) Acquired and inherited lipodystrophies. N Engl J Med 350:1220–1234CrossRefPubMedGoogle Scholar
  2. 2.
    Hegele RA, Kraw ME, Ban MR, Miskie BA, Huff MW, Cao H (2003) Elevated serum C-reactive protein and free fatty acids among nondiabetic carriers of missense mutations in the gene encoding lamin A/C (LMNA) with partial lipodystrophy. Arterioscler Thromb Vasc Biol 23:111–116CrossRefPubMedGoogle Scholar
  3. 3.
    Hegele RA (2001) Premature atherosclerosis associated with monogenic insulin resistance. Circulation 103:2225–2229PubMedGoogle Scholar
  4. 4.
    Mohamed-Ali V, Pinkney JH, Coppack SW (1998) Adipose tissue as an endocrine and paracrine organ. Int J Obes Relat Metab Disord 22:1145–1158CrossRefPubMedGoogle Scholar
  5. 5.
    Haque WA, Shimomura I, Matsuzawa Y, Garg A (2002) Serum adiponectin and leptin levels in patients with lipodystrophies. J Clin Endocrinol Metab 87:2395CrossRefPubMedGoogle Scholar
  6. 6.
    Yamauchi T, Kamon J, Waki H et al (2001) The fat-derived hormone adiponectin reverses insulin resistance associated with both lipoatrophy and obesity. Nat Med 7:941–946CrossRefPubMedGoogle Scholar
  7. 7.
    Lihn AS, Richelsen B, Pedersen SB et al (2003) Increased expression of TNF-alpha, IL-6, and IL-8 in HALS: implications for reduced adiponectin expression and plasma levels. Am J Physiol Endocrinol Metab 285:E1072–E1080PubMedGoogle Scholar
  8. 8.
    Johnson JA, Albu JB, Engelson ES et al (2004) Increased systemic and adipose tissue cytokines in patients with HIV-associated lipodystrophy. Am J Physiol Endocrinol Metab 286:E261–E271CrossRefPubMedGoogle Scholar
  9. 9.
    Vigouroux C, Maachi M, Nguyen TH et al (2003) Serum adipocytokines are related to lipodystrophy and metabolic disorders in HIV-infected men under antiretroviral therapy. AIDS 17:1503–1511CrossRefPubMedGoogle Scholar
  10. 10.
    Iglesias P, Alvarez FP, Codoceo R, Diez JJ (2004) Lipoatrophic diabetes in an elderly woman: clinical course and serum adipocytokine concentrations. Endocr J 51:279–286CrossRefPubMedGoogle Scholar
  11. 11.
    Jan V, Cervera P, Maachi M et al (2004) Altered fat differentiation and adipocytokine expression are inter-related and linked to morphological changes and insulin resistance in HIV-1-infected lipodystrophic patients. Antivir Ther 9:555–564PubMedGoogle Scholar
  12. 12.
    Shackleton S, Lloyd DJ, Jackson SN et al (2000) LMNA, encoding lamin A/C, is mutated in partial lipodystrophy. Nat Genet 24:153–156CrossRefPubMedGoogle Scholar
  13. 13.
    Jackson SN, Pinkney J, Bargiotta A et al (1998) A defect in the regional deposition of adipose tissue (partial lipodystrophy) is encoded by a gene at chromosome 1q. Am J Hum Genet 63:534–540CrossRefPubMedGoogle Scholar
  14. 14.
    Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC (1985) Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 28:412–419CrossRefPubMedGoogle Scholar
  15. 15.
    Hotta K, Funahashi T, Arita Y et al (2000) Plasma concentrations of a novel, adipose-specific protein, adiponectin, in type 2 diabetic patients. Arterioscler Thromb Vasc Biol 20:1595–1599PubMedGoogle Scholar
  16. 16.
    Weyer C, Funahashi T, Tanaka S et al (2001) Hypoadiponectinemia in obesity and type 2 diabetes: close association with insulin resistance and hyperinsulinemia. J Clin Endocrinol Metab 86:1930–1935CrossRefPubMedGoogle Scholar
  17. 17.
    Kern PA, Di Gregorio GB, Lu T, Rassouli N, Ranganathan G (2003) Adiponectin expression from human adipose tissue: relation to obesity, insulin resistance, and tumor necrosis factor-alpha expression. Diabetes 52:1779–1785PubMedCrossRefGoogle Scholar
  18. 18.
    Fernandez-Real JM, Lopez-Bermejo A, Casamitjana R, Ricart W (2003) Novel interactions of adiponectin with the endocrine system and inflammatory parameters. J Clin Endocrinol Metab 88:2714–2718CrossRefPubMedGoogle Scholar
  19. 19.
    Bruun JM, Lihn AS, Verdich C et al (2003) Regulation of adiponectin by adipose tissue-derived cytokines: in vivo and in vitro investigations in humans. Am J Physiol Endocrinol Metab 285:E527–E533PubMedGoogle Scholar
  20. 20.
    Ruan H, Lodish HF (2003) Insulin resistance in adipose tissue: direct and indirect effects of tumor necrosis factor-alpha. Cytokine Growth Factor Rev 14:447–455CrossRefPubMedGoogle Scholar
  21. 21.
    Arita Y, Kihara S, Ouchi N et al (1999) Paradoxical decrease of an adipose-specific protein, adiponectin, in obesity. Biochem Biophys Res Commun 257:79–83CrossRefPubMedGoogle Scholar
  22. 22.
    Cnop M, Havel PJ, Utzschneider KM et al (2003) Relationship of adiponectin to body fat distribution, insulin sensitivity and plasma lipoproteins: evidence for independent roles of age and sex. Diabetologia 46:459–469PubMedGoogle Scholar
  23. 23.
    Yang WS, Lee WJ, Funahashi T et al (2001) Weight reduction increases plasma levels of an adipose-derived anti-inflammatory protein, adiponectin. J Clin Endocrinol Metab 86:3815–3819CrossRefPubMedGoogle Scholar
  24. 24.
    Yatagai T, Nagasaka S, Taniguchi A et al (2003) Hypoadiponectinemia is associated with visceral fat accumulation and insulin resistance in Japanese men with type 2 diabetes mellitus. Metabolism 52:1274–1278CrossRefPubMedGoogle Scholar
  25. 25.
    Abbasi F, Chu JW, Lamendola C et al (2004) Discrimination between obesity and insulin resistance in the relationship with adiponectin. Diabetes 53:585–590PubMedCrossRefGoogle Scholar
  26. 26.
    Kern PA, Di Gregorio GB, Lu T, Rassouli N, Ranganathan G (2003) Adiponectin expression from human adipose tissue: relation to obesity, insulin resistance, and tumor necrosis factor-alpha expression. Diabetes 52:1779–1785PubMedCrossRefGoogle Scholar
  27. 27.
    Lindsay RS, Funahashi T, Hanson RL et al (2002) Adiponectin and development of type 2 diabetes in the Pima Indian population. Lancet 360:57–58CrossRefPubMedGoogle Scholar
  28. 28.
    Matsubara M, Maruoka S, Katayose S (2002) Decreased plasma adiponectin concentrations in women with dyslipidemia. J Clin Endocrinol Metab 87:2764–2769CrossRefPubMedGoogle Scholar
  29. 29.
    Shimada K, Miyazaki T, Daida H (2004) Adiponectin and atherosclerotic disease. Clin Chim Acta 344:1–12CrossRefPubMedGoogle Scholar
  30. 30.
    Fasshauer M, Klein J, Neumann S, Eszlinger M, Paschke R (2002) Hormonal regulation of adiponectin gene expression in 3T3-L1 adipocytes. Biochem Biophys Res Commun 290:1084–1089CrossRefPubMedGoogle Scholar
  31. 31.
    Maeda N, Takahashi M, Funahashi T et al (2001) PPARgamma ligands increase expression and plasma concentrations of adiponectin, an adipose-derived protein. Diabetes 50:2094–2099PubMedCrossRefGoogle Scholar
  32. 32.
    Ruan H, Hacohen N, Golub TR, Van PL, Lodish HF (2002) Tumor necrosis factor-alpha suppresses adipocyte-specific genes and activates expression of preadipocyte genes in 3T3-L1 adipocytes: nuclear factor-kappaB activation by TNF-alpha is obligatory. Diabetes 51:1319–1336PubMedCrossRefGoogle Scholar
  33. 33.
    Ruan H, Miles PD, Ladd CM et al (2002) Profiling gene transcription in vivo reveals adipose tissue as an immediate target of tumor necrosis factor-alpha: implications for insulin resistance. Diabetes 51:3176–3188PubMedCrossRefGoogle Scholar
  34. 34.
    Maeda N, Shimomura I, Kishida K et al (2002) Diet-induced insulin resistance in mice lacking adiponectin/ACRP30. Nat Med 8:731–737CrossRefPubMedGoogle Scholar
  35. 35.
    Yokota T, Oritani K, Takahashi I et al (2000) Adiponectin, a new member of the family of soluble defense collagens, negatively regulates the growth of myelomonocytic progenitors and the functions of macrophages. Blood 96:1723–1732PubMedGoogle Scholar
  36. 36.
    Shimomura I, Hammer RE, Ikemoto S, Brown MS, Goldstein JL (1999) Leptin reverses insulin resistance and diabetes mellitus in mice with congenital lipodystrophy. Nature 401:73–76CrossRefPubMedGoogle Scholar
  37. 37.
    Shimomura I, Hammer RE, Richardson JA et al (1998) Insulin resistance and diabetes mellitus in transgenic mice expressing nuclear SREBP-1c in adipose tissue: model for congenital generalized lipodystrophy. Genes Dev 12:3182–3194PubMedGoogle Scholar
  38. 38.
    Tsuboyama-Kasaoka N, Takahashi M, Tanemura K et al (2000) Conjugated linoleic acid supplementation reduces adipose tissue by apoptosis and develops lipodystrophy in mice. Diabetes 49:1534–1542PubMedCrossRefGoogle Scholar
  39. 39.
    Motoshima H, Wu X, Sinha MK et al (2002) Differential regulation of adiponectin secretion from cultured human omental and subcutaneous adipocytes: effects of insulin and rosiglitazone. J Clin Endocrinol Metab 87:5662–5667CrossRefPubMedGoogle Scholar
  40. 40.
    Haque WA, Vuitch F, Garg A (2002) Post-mortem findings in familial partial lipodystrophy, Dunnigan variety. Diabet Med 19:1022–1025CrossRefPubMedGoogle Scholar
  41. 41.
    Mohamed-Ali V, Goodrick S, Rawesh A et al (1997) Subcutaneous adipose tissue releases interleukin-6, but not tumor necrosis factor-alpha, in vivo. J Clin Endocrinol Metab 82:4196–4200CrossRefPubMedGoogle Scholar
  42. 42.
    Kern PA, Ranganathan S, Li C, Wood L, Ranganathan G (2001) Adipose tissue tumor necrosis factor and interleukin-6 expression in human obesity and insulin resistance. Am J Physiol Endocrinol Metab 280:E745–E751PubMedGoogle Scholar
  43. 43.
    Engeli S, Feldpausch M, Gorzelniak K et al (2003) Association between adiponectin and mediators of inflammation in obese women. Diabetes 52:942–947PubMedCrossRefGoogle Scholar
  44. 44.
    Carey AL, Febbraio MA (2004) Interleukin-6 and insulin sensitivity: friend or foe? Diabetologia 47:1135–1142PubMedGoogle Scholar
  45. 45.
    Vozarova B, Weyer C, Hanson K, Tataranni PA, Bogardus C, Pratley RE (2001) Circulating interleukin-6 in relation to adiposity, insulin action, and insulin secretion. Obes Res 9:414–417PubMedCrossRefGoogle Scholar
  46. 46.
    Carey AL, Bruce CR, Sacchetti M et al (2004) Interleukin-6 and tumor necrosis factor-alpha are not increased in patients with type 2 diabetes: evidence that plasma interleukin-6 is related to fat mass and not insulin responsiveness. Diabetologia 47:1029–1037PubMedGoogle Scholar
  47. 47.
    Flower L, Gray R, Pinkney J, Mohamed-Ali V (2003) Stimulation of interleukin-6 release by interleukin-1beta from isolated human adipocytes. Cytokine 21:32–37CrossRefPubMedGoogle Scholar
  48. 48.
    Memon RA, Feingold KR, Moser AH, Fuller J, Grunfeld C (1998) Regulation of fatty acid transport protein and fatty acid translocase mRNA levels by endotoxin and cytokines. Am J Physiol Endocrinol Metab 274:E210–E217Google Scholar
  49. 49.
    Lihn AS, Bruun JM, He G, Pedersen SB, Jensen PF, Richelsen B (2004) Lower expression of adiponectin mRNA in visceral adipose tissue in lean and obese subjects. Mol Cell Endocrinol 219:9–15CrossRefPubMedGoogle Scholar
  50. 50.
    Bruun JM, Pedersen SB, Kristensen K, Richelsen B (2002) Effects of pro-inflammatory cytokines and chemokines on leptin production in human adipose tissue in vitro. Mol Cell Endocrinol 190:91–99CrossRefPubMedGoogle Scholar
  51. 51.
    Steppan CM, Bailey ST, Bhat S et al (2001) The hormone resistin links obesity to diabetes. Nature 409:307–312CrossRefPubMedGoogle Scholar
  52. 52.
    Banerjee RR, Rangwala SM, Shapiro JS et al (2004) Regulation of fasted blood glucose by resistin. Science 303:1195–1198CrossRefPubMedGoogle Scholar
  53. 53.
    Rea R, Donnelly R (2004) Resistin: an adipocyte-derived hormone. Has it a role in diabetes and obesity? Diabetes Obes Metab 6:163–170CrossRefPubMedGoogle Scholar
  54. 54.
    Degawa-Yamauchi M, Bovenkerk JE, Juliar BE et al (2003) Serum resistin (FIZZ3) protein is increased in obese humans. J Clin Endocrinol Metab 88:5452–5455CrossRefPubMedGoogle Scholar
  55. 55.
    Bouchard L, Weisnagel SJ, Engert JC et al (2004) Human resistin gene polymorphism is associated with visceral obesity and fasting and oral glucose stimulated C-peptide in the Quebec Family Study. J Endocrinol Invest 27:1003–1009PubMedGoogle Scholar
  56. 56.
    Chen CC, Li TC, Li CI, Liu CS, Wang HJ, Lin CC (2005) Serum resistin level among healthy subjects: relationship to anthropometric and metabolic parameters. Metabolism 54:471–475CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag 2005

Authors and Affiliations

  • S. P. Y. Wong
    • 1
  • M. Huda
    • 1
  • P. English
    • 1
  • A. Bargiotta
    • 2
  • J. P. H. Wilding
    • 1
  • A. Johnson
    • 3
  • R. Corrall
    • 2
  • J. H. Pinkney
    • 1
    • 4
    Email author
  1. 1.Clinical Sciences CentreUniversity Hospital AintreeLiverpoolUK
  2. 2.Diabetes and EndocrinologyBristol Royal InfirmaryBristolUK
  3. 3.Diabetes CentreSouthmead HospitalBristolUK
  4. 4.Department of MedicineRoyal Cornwall HospitalTruroUK

Personalised recommendations