A previous study reported the increased expression of the cytokine TNF in the adipose tissue of genetically obese rodents. To examine this paradigm in humans, we studied TNF expression in lean, obese, and reduced-obese human subjects. TNF mRNA was demonstrated in human adipocytes and adipose tissue by Northern blotting and PCR. TNF protein was quantitated by Western blotting and ELISA in both adipose tissue and the medium surrounding adipose tissue. Using quantitative reverse transcriptase PCR (RT-PCR), TNF mRNA levels were examined in the adipose tissue of 39 nondiabetic subjects, spanning a broad range of body mass index (BMI). There was a significant increase in adipose TNF mRNA levels with increasing adiposity. There was a significant correlation between TNF mRNA and percent body fat (r = 0.46, P < 0.05, n = 23). TNF mRNA tended to decrease in very obese subjects, but when subjects with a BMI > 45 kg/m2 were excluded, there was a significant correlation between TNF mRNA and BMI (r = 0.37, P < 0.05, n = 32). In addition, there was a significant decrease in adipose TNF with weight loss. In 11 obese subjects who lost between 14 and 66 kg (mean 34.7 kg, or 26.6% of initial weight), TNF mRNA levels decreased to 58% of initial levels after weight loss (P < 0.005), and TNF protein decreased to 46% of initial levels (P < 0.02). TNF is known to inhibit LPL activity. When fasting adipose LPL activity was measured in these subjects, there was a significant inverse relationship between TNF expression and LPL activity (r = -0.39, P < 0.02, n = 39). With weight loss, LPL activity increased to 411% of initial levels. However, the magnitude of the increase in LPL did not correlate with the decrease in TNF. Thus, TNF is expressed in human adipocytes. TNF is elevated in most obese subjects and is decreased by weight loss. In addition, there is an inverse relationship between TNF and LPL expression. These data suggest that endogenous TNF expression in adipose tissue may help limit obesity in some subjects, perhaps by increasing insulin resistance and decreasing LPL. (J. Clin. Invest. 1995. 95:2111-2119
IntroductionTo study the mechanism of lipoprotein lipase (LPL) regulation by exercise, we recruited 16 healthy athletes to undergo a 2-wk period of detraining. Fasting fat and muscle biopsies were performed both before and after the detraining period. In muscle, detraining resulted in a decrease in LPL activity in both the heparin-releasable (HR) (-45%, P < 0.05) and cellular (ex- Triglyceride-derived FFA are taken up by tissues through the action oflipoprotein lipase (LPL)'(1), which is found predominantly in adipose tissue and muscle. In human adipose tissue, little FFA is synthesized from glucose, and therefore LPL is an important enzyme for lipid storage (2). In contrast, muscle uses FFA for oxidation (3). The LPL found in both adipose tissue and muscle contributes to the clearance of circulating triglyceride-rich lipoproteins.Previous studies have examined the effects of exercise on LPL activity, using a number of different exercise regimens (reviewed in reference 4). Studies of endurance training in human subjects showed significant increases in LPL activity, both in skeletal muscle and adipose tissue, as well as in postheparin plasma. Weight loss also yields increases in adipose LPL (5), however, and many studies of exercise did not control for weight loss during the exercise regimen. Kiens et al. (6) studied six healthy men in which LPL activity was measured in the knee extensors at rest and after 8 wk of training of one leg, while the other leg was not exercised and served as a control. They found a 70% increase in LPL activity in the trained leg compared with the nontrained one.A number of previous studies have examined the mechanism of LPL regulation, and have discovered that LPL may be regulated at multiple different cellular sites (7). This study was designed to examine the mechanism of regulation of LPL by exercise in adipose tissue and muscle. As described below, short-term changes in exercise altered LPL activity in both tissues through posttranslational changes. Methods Recruitment ofstudy subjects. 16 subjects (10 men and 6 women; age, 37±2 yr) were recruited for this study, and their characteristics are shown in Table I. All subjects were in good health, were taking no medications, and were running 2 32 km/wk, or performing an equivalent amount of aerobic exercise (one subject bicycled -600 km/ week). 6 of the 16 subjects ran a marathon within 1 mo preceding the study. To participate in the study, the subjects had to agree to detrain for 2 wk, and gave informed consent to the procedures. Detraining entailed no aerobic exercise, but just activities of daily living. Compliance with these instructions was judged to be excellent. This protocol was approved by the Internal Review Board of Cedars-Sinai Medical Center, and subjects gave informed consent to the procedures.
Renal functional reserve, microalbuminuria, and plasma atrial natriuretic factor were measured in 21 offspring (9.5 +/- 0.5 years of age, mean +/- SEM) of hypertensive parents and in eight children (10 +/- 0.5 years of age) with no family history of hypertension who were used as a control group. Renal functional reserve was evaluated by measurement of the changes in creatinine clearance after an oral protein load of 45 g/m2. Atrial natriuretic factor levels were determined before and 60 minutes after the protein load, and microalbuminuria in fractional urine before and 120 minutes after the same stimulus as well as in a 24-hour urine collection. All children in the control group significantly increased their creatinine clearance after the protein load (preload, 122 +/- 12; 60 minutes, 144 +/- 9; 120 minutes, 154 +/- 11; 180 minutes, 144 +/- 9 ml/min/1.73 m2; all values were significant vs. preload, p less than 0.005). In contrast, only 13 of 21 offspring of hypertensive parents increased their creatinine clearance to values within 2 SD of the increase shown by the control group (preload, 144 +/- 11; 60 minutes, 153 +/- 7; 120 minutes, 202 +/- 13 ml/min/1.73 m2; p less than 0.001 vs. preload; 180 minutes, 214 +/- 19 ml/min/1.73 m2, p less than 0.001 vs. preload). The remaining eight offspring of hypertensive parents showed no detectable changes (nonresponders) (preload, 189 +/- 18; 60 minutes, 146 +/- 11; 120 minutes, 170 +/- 14; 180 minutes, 168 +/- 13 ml/min/1.73 m2; all values p = NS). No changes in atrial natriuretic factor after the protein load were observed in any group. Offspring of hypertensive parents presented higher microalbuminuria levels in 24-hour urine specimens (3.1 micrograms/min, tolerance factor [TF]2.2) than controls (2.1 micrograms/min, TF 1.5) (p less than 0.05). Although microalbuminuria increased significantly after the water load in the control group (p less than 0.05) and in the offspring of hypertensive parents (p less than 0.01), it returned to baseline at 120 minutes in the former but not in the latter (p less than 0.05 vs. baseline). The lack of renal functional reserve in nonresponders was significantly related (p less than 0.05) to the presence of higher levels of microalbuminuria. We conclude that the absence of renal functional reserve and increased microalbuminuria in some normotensive children who are offspring of essential hypertensive parents can indicate that subtle alterations in renal function may precede the onset of clinical hypertension.
Family history of hypertension and obesity are both risk factors for hypertension. Hypertension and obesity share several physiopathologic abnormalities and are frequently associated. However, not all obese people are hypertensive. Renal handling of sodium has been proposed as a physiopathogenic mechanism of essential hypertension and obesity. This study was conducted in obese adolescents to evaluate the role of a family history of hypertension versus obesity in the renal handling of sodium. .5% ؎ 1.3%, in ON it was 22.4% ؎ 2.3%, and in LH it was 14.4% ؎ 1.2% (P < .05). FEUA in OH was 8.5% ؎ 0.8%, in ON it was 14.8% ؎ 3.6%, and in LH it was 7.9% ؎ 0.8% (P < .01). Plasma renin activity (PRA) and aldosterone (PA) were measured in OH and LH; PRA was 5.3 ؎ 0.4 and 4.5 ؎ 0.4 ng/mL/h, respectively (P ؍ NS), and PA was 366 ؎ 36 and 242 ؎ 32 pg/mL, respectively (P < .05). In summary, adolescents with a family history of hypertension, regardless of their body mass, have a diminished FELi and FEUA. Obese adolescents also have higher plasma levels of aldosterone than lean ones. In conclusion, the family history of hypertension would be related to the increased renal proximal sodium reabsorption whereas obesity would be related to increased distal sodium reabsorption mechanisms, such as aldosterone. Both mechanisms could explain the higher prevalence of hypertension in obese offspring of hypertensive parents. Am J Hypertens 1999;12:260 -263
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