Adipocyte Metabolism in Endogenous Hypertriglyceridemia BoLarsson,
Per Bjiirntorp,
Jan Holm, Tore Scherstb,
Lars SjSstrlim,
and
In order to define specific metabolic abnormalities of adipose tissue metabolism in endogenous hypertriglyceridemia (EH) patients with this condition were comnormolipidemic pared with controls matched for body fat and fat cell size. In vitro the enlarged fat cells of EH were found to have an increased basal and noradrenaline-stimulated lipolysir in comparison with cells of the same size from normolipidemic controls. The insulin inhibition of noradrenaline-stimulated lipolysis was blunted. lipoprotein lipase activity in these cells was clearly depressed. Basal triglyceride synthesis from labeled glucose was low in relation to plasma insulin. The reduction of insulin tolerance in vivo suggested that the depression of plasma glycerol and free fatty acid con-
Ulf Smith
centration was small in EH, suggesting that the more detailed findings in vitro were of relevance for in vivo conditions. It was suggested that the hyperinsulinemia and decreased glucose tolemnce of EH may well be responsible for some of the aberrations of adipocyte metabolism in EH. The decreased responsiveness of lipolysis to insulin and the low lipoprotein lipase activity are, however, findings not typical for enlarged fat cells exposed chronically to insulin and might be characteristicfor the fat cells of EH. It seems of importance to further define the factor(s) responsible for these metabolic aberrations, because the abnormalities of the acipocyte metabolism in EH may well offer a possible explanation to the pathogenesis of that condition.
A
N ASSOCIATION between endogenous hypertriglyceridemia (EH) and obesity has been demonstrated in several reports.‘4 The reason for this association is, however, not clear.5 Apparently EH is more closely connected with a recent weight increase3”’ rather than with the mass of the adipose tissue, because patients preselected for obesity usually seem to have only moderately elevated plasma triglyceride levels.6~*~9 Recent examinations of adipose tissue cellularity have shown that the moderate obesity of EH is associated with enlarged fat cells rather than with an increase in fat cell number.“*” The later debut of the hypertrophic obesity’2*‘3 is in line with the observed associations between EH and recent weight gain?*6*7 The large fat cells in EH focus the interest on adipose tissue metabolism in this condition, because it has been repeatedly described that enlargement of fat cells causes an increase in basal metabolism’4*‘5 and also influences the cellular responsiveness to hormones.16*” Adipose tissue from subjects with EH has been studied before in the basal state by Kuo et al.r8 and by Walldius et a1.r9 The latter authors showed a decreased incorporation of labeled palmitate and From the Clinical Metabolic Laboratory of the First and Second Medical Services and from the Second Surgical Service, Sahlgren’s Hospital, University of Gothenburg. Gothenburg. Sweden. Receivedfor publication February 25. 197s. Supported by grants B75-19X-25I-I3A and B75-19X-3506 from the Swedish Medical Research Council andfrom the Swedish National Association against Heart and Chest Diseases. Reprint requests should be addressed to Dr. Per Bjiirntorp. First Medical Service, Sahlgren’s Hospital. S-413 45 Gothenburg. Sweden. 0 1975 by Grune & Stratton, Inc.
Metabolism, Vol. 24, No. 12 (December). 1975
1375
1376
LARSSON
ET AL.
glucose from the incubation medium into the adipose tissue triglycerides. However, in none of these studies was the cellular character of the adipose tissue defined and, therefore, findings typical for the enlarged fat cells of EH could not be separated from effects of cell enlargement per se. Recently, we investigated the metabolism of the adipose tissue from a few subjects with hyperlipidemia.” However, the findings of that study may not be truly representative for the hyperlipidemic state since the subjects were fed a diet rich in carbohydrate which in turn influences the metabolism of the fat cefls.2’-23 Several reports on elevated concentrations and turn-over rates of plasma free fatty acids (FFA) or free glycerol in obesity have been published (for review, see 24). In EH the available results seem more difficult to interpret. Adams FFA concenet a1.25 have recent 1y studied this problem and found increased tration and turn-over rate in the over-night fasting state while this has not been found by other investigators. 2628 However, it is not clear from any of these studies whether the findings were typical for EH or simply due to the obesity associated with the hypertriglyceridemia because body fat and fat cell size were not determined. In the present work an effort was made to circumvent these problems by making comparisons between groups with equal obesity with or without EH. In this way observations typical for EH could be made. Furthermore, the metabolism of the adipocytes in vitro from EH patients and reference groups was analysed and compared at equal fat cell sizes. MATERIALS
AND METHODS
From population studies of randomly selected men in Gothenburg born 1913 and 1923, ten subjects with EH were selected for examination with respect to all in vivo and in vitro parameters given later in this section. EH was defined as follows: Plasma triglyceride concentration above 172 mg/lOO ml (2.0 mM glyceride glycerol) on at least two occasions and the presence of a clear prebeta band on agarose lipoprotein electrophoresis and absence of chylomicra.29*sc The average triglyceride concentration was 241 mg/lOO ml (range 173-330 mg/lOO ml). The EH subjects were otherwise healthy and took no drugs on a regular basis. There was no evidence of alcohol abuse. Their hypertriglyceridemia was discovered in the population examinations and none of the subjects was on a diet. The EH material was compared with different control groups (see the following sections), which were selected from a pool of altogether 51 non-EH controls. All these subjects had a plasma triglyceride concentration below 140 mg/lOO ml (1.6 mM glyceride glycerol). No prebeta bands were demonstrable. Of the 51 subjects, 20 were healthy men from the same population studies and I4 were other healthy volunteers. The remaining 17 subjects were operated on for nonmalignant abdominal diseases. Except for a moderate obesity in some cases the controls had no metabolic disturbances. All reference subjects were in a caloric steady state as judged from histories of diet and body weight. Since several of the healthy subjects from the population studies did not accept surgical biopsies, adipose tissue metabolism in vitro was not possible to examine in these cases except lipoprotein lipase activity, which was analysed in needle biopsies. Therefore, from the pool of 51 reference subjects, subgroups were selected according to the following principles: (I) For experiments not involving adipose tissue metabolism in vitro, that is, in experiments reported in Fig. 1 and Table 2, two reference groups were selected. One group consisted of I4 subjects, all with a normal body fat i.e., within mean f 2 SD of the body fat of randomly selected men born 1913.3’ The other reference ilar to that of the EH group. All matched mean f 2 SD of the EH group.
group was selected so that their body fat was simreference subjects (n = 20) had a body fat within
ADIPOCYTE
METABOLISM
80 INSULIN &U/ml)
I
GLYCEROL
Fig.
1. plasma insulin, glueore, and fne fatty acid concentmtions during an insulin tolomnco test in patients with endogenour hypertriglyceridemia (El-l) (solid lines), in controls with body fat matched to tha patients with endogenous hypertriglyceridemia (FC) (broken lines), and in controls with normal body fat (LC) (dotted lines). Means I SEM.
glycerol,
FREE
FATTY
;
;
;
ACIDS
(mM)
r/F
15 30 45
90
Minutes
Statistical Analysis of Figum 1. 0
30
15
45
90 min
Insulin Eli vs FC EH vs LC FC vs LC
“S
Per Bjiirntorp,
Jan Holm, Tore Scherstb,
Lars SjSstrlim,
and
In order to define specific metabolic abnormalities of adipose tissue metabolism in endogenous hypertriglyceridemia (EH) patients with this condition were comnormolipidemic pared with controls matched for body fat and fat cell size. In vitro the enlarged fat cells of EH were found to have an increased basal and noradrenaline-stimulated lipolysir in comparison with cells of the same size from normolipidemic controls. The insulin inhibition of noradrenaline-stimulated lipolysis was blunted. lipoprotein lipase activity in these cells was clearly depressed. Basal triglyceride synthesis from labeled glucose was low in relation to plasma insulin. The reduction of insulin tolerance in vivo suggested that the depression of plasma glycerol and free fatty acid con-
Ulf Smith
centration was small in EH, suggesting that the more detailed findings in vitro were of relevance for in vivo conditions. It was suggested that the hyperinsulinemia and decreased glucose tolemnce of EH may well be responsible for some of the aberrations of adipocyte metabolism in EH. The decreased responsiveness of lipolysis to insulin and the low lipoprotein lipase activity are, however, findings not typical for enlarged fat cells exposed chronically to insulin and might be characteristicfor the fat cells of EH. It seems of importance to further define the factor(s) responsible for these metabolic aberrations, because the abnormalities of the acipocyte metabolism in EH may well offer a possible explanation to the pathogenesis of that condition.
A
N ASSOCIATION between endogenous hypertriglyceridemia (EH) and obesity has been demonstrated in several reports.‘4 The reason for this association is, however, not clear.5 Apparently EH is more closely connected with a recent weight increase3”’ rather than with the mass of the adipose tissue, because patients preselected for obesity usually seem to have only moderately elevated plasma triglyceride levels.6~*~9 Recent examinations of adipose tissue cellularity have shown that the moderate obesity of EH is associated with enlarged fat cells rather than with an increase in fat cell number.“*” The later debut of the hypertrophic obesity’2*‘3 is in line with the observed associations between EH and recent weight gain?*6*7 The large fat cells in EH focus the interest on adipose tissue metabolism in this condition, because it has been repeatedly described that enlargement of fat cells causes an increase in basal metabolism’4*‘5 and also influences the cellular responsiveness to hormones.16*” Adipose tissue from subjects with EH has been studied before in the basal state by Kuo et al.r8 and by Walldius et a1.r9 The latter authors showed a decreased incorporation of labeled palmitate and From the Clinical Metabolic Laboratory of the First and Second Medical Services and from the Second Surgical Service, Sahlgren’s Hospital, University of Gothenburg. Gothenburg. Sweden. Receivedfor publication February 25. 197s. Supported by grants B75-19X-25I-I3A and B75-19X-3506 from the Swedish Medical Research Council andfrom the Swedish National Association against Heart and Chest Diseases. Reprint requests should be addressed to Dr. Per Bjiirntorp. First Medical Service, Sahlgren’s Hospital. S-413 45 Gothenburg. Sweden. 0 1975 by Grune & Stratton, Inc.
Metabolism, Vol. 24, No. 12 (December). 1975
1375
1376
LARSSON
ET AL.
glucose from the incubation medium into the adipose tissue triglycerides. However, in none of these studies was the cellular character of the adipose tissue defined and, therefore, findings typical for the enlarged fat cells of EH could not be separated from effects of cell enlargement per se. Recently, we investigated the metabolism of the adipose tissue from a few subjects with hyperlipidemia.” However, the findings of that study may not be truly representative for the hyperlipidemic state since the subjects were fed a diet rich in carbohydrate which in turn influences the metabolism of the fat cefls.2’-23 Several reports on elevated concentrations and turn-over rates of plasma free fatty acids (FFA) or free glycerol in obesity have been published (for review, see 24). In EH the available results seem more difficult to interpret. Adams FFA concenet a1.25 have recent 1y studied this problem and found increased tration and turn-over rate in the over-night fasting state while this has not been found by other investigators. 2628 However, it is not clear from any of these studies whether the findings were typical for EH or simply due to the obesity associated with the hypertriglyceridemia because body fat and fat cell size were not determined. In the present work an effort was made to circumvent these problems by making comparisons between groups with equal obesity with or without EH. In this way observations typical for EH could be made. Furthermore, the metabolism of the adipocytes in vitro from EH patients and reference groups was analysed and compared at equal fat cell sizes. MATERIALS
AND METHODS
From population studies of randomly selected men in Gothenburg born 1913 and 1923, ten subjects with EH were selected for examination with respect to all in vivo and in vitro parameters given later in this section. EH was defined as follows: Plasma triglyceride concentration above 172 mg/lOO ml (2.0 mM glyceride glycerol) on at least two occasions and the presence of a clear prebeta band on agarose lipoprotein electrophoresis and absence of chylomicra.29*sc The average triglyceride concentration was 241 mg/lOO ml (range 173-330 mg/lOO ml). The EH subjects were otherwise healthy and took no drugs on a regular basis. There was no evidence of alcohol abuse. Their hypertriglyceridemia was discovered in the population examinations and none of the subjects was on a diet. The EH material was compared with different control groups (see the following sections), which were selected from a pool of altogether 51 non-EH controls. All these subjects had a plasma triglyceride concentration below 140 mg/lOO ml (1.6 mM glyceride glycerol). No prebeta bands were demonstrable. Of the 51 subjects, 20 were healthy men from the same population studies and I4 were other healthy volunteers. The remaining 17 subjects were operated on for nonmalignant abdominal diseases. Except for a moderate obesity in some cases the controls had no metabolic disturbances. All reference subjects were in a caloric steady state as judged from histories of diet and body weight. Since several of the healthy subjects from the population studies did not accept surgical biopsies, adipose tissue metabolism in vitro was not possible to examine in these cases except lipoprotein lipase activity, which was analysed in needle biopsies. Therefore, from the pool of 51 reference subjects, subgroups were selected according to the following principles: (I) For experiments not involving adipose tissue metabolism in vitro, that is, in experiments reported in Fig. 1 and Table 2, two reference groups were selected. One group consisted of I4 subjects, all with a normal body fat i.e., within mean f 2 SD of the body fat of randomly selected men born 1913.3’ The other reference ilar to that of the EH group. All matched mean f 2 SD of the EH group.
group was selected so that their body fat was simreference subjects (n = 20) had a body fat within
ADIPOCYTE
METABOLISM
80 INSULIN &U/ml)
I
GLYCEROL
Fig.
1. plasma insulin, glueore, and fne fatty acid concentmtions during an insulin tolomnco test in patients with endogenour hypertriglyceridemia (El-l) (solid lines), in controls with body fat matched to tha patients with endogenous hypertriglyceridemia (FC) (broken lines), and in controls with normal body fat (LC) (dotted lines). Means I SEM.
glycerol,
FREE
FATTY
;
;
;
ACIDS
(mM)
r/F
15 30 45
90
Minutes
Statistical Analysis of Figum 1. 0
30
15
45
90 min
Insulin Eli vs FC EH vs LC FC vs LC
“S
