Growth hormone action in puberty: Effects by gender

OBJECTIVE: Adult females receiving GH may be less sensitive to the metabolic effects of GH than males, however these differences are less well studied in adolescence. We aimed to investigate if metabolic effects of GH vary by gender during puberty. DESIGN: Sixteen adolescents (8 M/8 F, mean age (SE): 13.1+/-0.2 yr) with significant short stature due to either GH insufficiency or idiopathic short stature were studied before and after 8 w of daily GH therapy. Differences in rates of protein and glycerol turnover ((13)C leucine and d5-glycerol infusions), substrate oxidation rates (indirect calorimetry), hormones, growth factors, lipid concentrations, body composition (DEXA) and 1 yr growth velocity were measured. RESULTS: Protein synthesis rates per kg FFM were similar in boys and girls before and after GH and increased similarly on treatment in both genders. Rates of whole body lipolysis were similar at baseline and increased after GH in both genders comparably. Plasma lipids were similar between boys and girls before and after GH, and triglycerides increased post-GH in both. Insulin increased after GH comparably in both genders, yet no significant difference in glucose or adiponectin concentrations during treatment or between genders was observed. IGF-I concentrations were similar between boys and girls at baseline, but with a more robust increase in males after 8 w of GH (boys: +629+/-65 ng/ml, girls: +331+/-67, p=0.007). Body composition changes and bone mineral density were similar between genders after GH. HT SDS increased comparably after 1 yr (boys -2.2+/-0.09 to -1.77+/-0.11, p=0.0002; girls -2.49+/-0.24 to -2.02+/-0.25, p=0.04). There were no gender differences on the linear growth responses after 12 mo. CONCLUSIONS: As compared to girls, boys had: (1) similar sensitivity to GH for protein synthesis, lipolysis, lipid concentrations and body composition changes as well as comparable glucose and adiponectin concentrations; (2) higher IGF-I responses to 8 w of GH. Differences in IGF-I during GH treatment may account in part for the gender differences in physique and strength that develop during human puberty; however, using conventional doses of GH, these differences do not translate into differences in linear growth after 12 mo. Contrary to adults, these data do not support the need for different GH dosing depending on gender during puberty.     

A Model of NEFA Dynamics with Focus on the Postprandial State

To improve the understanding of the mechanisms underlying the behavior of plasma non-esterified fatty acids (NEFA) in the postprandial state, we have developed a physiology-based mathematical model of plasma NEFA dynamics. Known physiological mechanisms are quantified and used to describe NEFA dynamics. Insulin is the major regulator of NEFA metabolism in the postprandial state. Plasma NEFA levels are thus highly dependent on the insulin concentration, the insulin sensitivity of adipose tissue, and the maximal lipolytic rate. In the postabsorptive state, e.g., at low insulin, adipose tissue lipolysis results in a net export of NEFA from adipose tissue to other tissues. Postprandially, the rise in insulin results in: Decreased lipolysis; a higher rate of lipoprotein lipase (LPL) activity; and decreased NEFA uptake and reesterification by adipose tissue stimulation of reesterification. The result is a drop in plasma NEFA after a carbohydrate containing meal. When insulin returns to postabsorptive levels, a rebound in plasma NEFA often occurs. This rebound is due to a restoration of lipolysis, a decrease in NEFA reesterification by adipose tissue and an increased LPL—as insulin activates LPL with a delay of several hours. In conclusion, movements of NEFA depend strongly on insulin—with postprandial plasma NEFA being almost inversely related to the insulin concentration in healthy humans. The model provides an integrative view of NEFA dynamics and a framework for quantitative and conceptual understanding of plasma NEFA fluxes.     

Exercise increases plasma THC concentrations in regular cannabis users

Background

The major psychoactive ingredient of cannabis, Δ⁹-tetrahydrocannabinol (THC) accumulates in fat tissue from where it slowly diffuses back into blood. THC pre-treated rats can show elevated plasma cannabinoid levels when subjected to conditions that promote fat utilization, such as fasting. Here we examine whether fasting and exercise increase plasma THC concentrations in regular cannabis users.

Methods

Fourteen regular cannabis users completed 35 min of exercise on a stationary bicycle in either a fed or overnight fasted state. Plasma cannabinoid levels were assessed prior to exercise, immediately post-exercise and 2 h post-exercise. Plasma samples were also analyzed for indices of lipolysis (free fatty acids (FFA) and glycerol).

Results

Exercise induced a small, statistically significant increase in plasma THC levels accompanied by increased plasma FFA and glycerol levels. Exercise-induced increases in plasma THC concentrations were positively correlated with body mass index. Fasting induced a significant increase in plasma FFA levels, and a lowering of blood glucose, but did not significantly alter plasma cannabinoid levels.

Conclusions

Here we demonstrate that exercise enhances plasma THC levels in regular cannabis users. The lack of a fasting effect may reflect the modest duration of fasting used which was associated with only a modest increase in fat utilization relative to exercise. Overall, these results suggest that exercise may elevate blood THC levels by releasing dormant THC from fat stores. These data suggest the interpretation of blood THC levels in roadside and workplace tests might be complicated by recent exercise.     

Role of vanadyl acetylacetonate-induced elevation of reactive oxygen species in the regulation of lipolysis and glucose metabolism in 3T3L1 adipocytes

In the present study, we investigated the role of reactive oxygen species (ROS) elevation induced by an anti-diabetic vanadium compound, vanadyl acetylacetonate (VO(acac)₂), in the regulation of lipolysis and glucose metabolism using differentiated 3T3L1 adipocytes as a model system. By confocal laser scanning microscopy, we found that VO(acac)₂ induced ROS generation under high glucose stimulation, and the pretreatment of NADPH oxidase inhibitors could significantly reduce the elevated ROS level. Meanwhile, the decreased phosphorylated levels of AKT and the two key modulators of lipolysis (HSL and perilipin) were observed by western blot analysis. We also found that the contents of glycerol release were further reduced as well. In addition, the levels of key regulatory proteins, AS160 and GSK3β, in glucose metabolism pathway were correspondingly reduced. These findings demonstrated that ROS induced by vanadium compounds could act as a metabolic signal to activate AKT pathway to inhibit lipolysis and promote glucose transport and glycogen synthesis rather than by direct action by themselves. Our study contributed to elucidate the anti-diabetic effects of vanadium compounds and provided a theoretical basis for the further development of new vanadium complexes in thepreventionandtherapeuticsof diabetes.     

Anti-lipase and lipolytic activities of ursolic acid isolated from the roots of <Emphasis Type="Italic">Actinidia arguta</Emphasis>

The aim of this study was to investigate the anti-obestic effects of ursolic acid isolated from the roots of Actinidia arguta, as well as the mechanism of action of this compound. This was conducted by testing whether ursolic acid inhibited the elevation of the rat plasma triacylglycerol levels after oral administration of a lipid emulsion containing corn oil in rats. Ursolic acid prevented the elevation of plasma triacylglycerol levels 2 h after oral administration of the lipid emulsion at a dose of 100 mg/kg. Furthermore, ursolic acid inhibited phosphodiesterase activity in vitro with an IC₅₀ of 51.21 μM and enhanced lipolysis in rat fat cells. We suggest that the inhibitory effects of ursolic acid, isolated from the roots of A. arguta, on obesity, might be attributable to the inhibition of lipid absorption through the inhibition of pancreatic lipase and by enhancing lipolysis in fat cells.     

Short-term effects of obestatin on hexose uptake and triacylglycerol breakdown in human subcutaneous adipocytes

AIM To study complete dose-dependent effects of obestatin on lipolytic and glucose transport activities in human adipocyte preparations highly responsive to insulin.METHODS Adipocytes were prepared by liberase digestion from subcutaneous abdominal adipose tissue obtained from overweight subjects undergoing plastic surgery. The index of lipolytic activity was the glycerol released in the incubation medium, while glucose transport was assessed by [~3H]-2-deoxyglucose uptake assay.RESULTS When tested from 0.1 nmol/L to 1 μmol/L, obestatin did not stimulate glycerol release; it did not inhibit the lipolytic effect of isoprenaline and did not alter the insulin antilipolytic effect. Obestatin hardly activated glucose transport at 1 μmol/L only. Moreover, the obestatin stimulation effect was clearly lower than the threefold increase induced by insulin 100 nmol/L.CONCLUSION Low doses of obestatin cannot directly influence lipolysis and glucose uptake in human fat cells.     

Adipose tissue distribution and risk of metabolic disease: does thiazolidinedione-induced adipose tissue redistribution provide a clue to the answer?

The relative effect of visceral and subcutaneous obesity on the risk of chronic metabolic disease has been a matter of long-term dispute. While ample data support either of the fat depots being causative or associative, valid argument for one depot often automatically belittles the other. Paradigms such as the visceral/portal hypothesis and the acquired lipodystrophy/ectopic fat storage and endocrine hypothesis have been proposed. Nevertheless, neither hypothesis alone explains the entire pathophysiological setting. Treatment of diabetes with thiazolidinediones selectively increases fat partitioning to the subcutaneous adipose depot but does not change visceral fat accumulation. This is in contrast to the preferential visceral fat mobilisation by diet and exercise. Surgical removal of visceral or subcutaneous adipose tissue yields relatively long-lasting metabolic improvement only when combined with procedures that ameliorate adipose tissue cell composition. These studies illustrate that human adipose tissue in different anatomic locations does not work in isolation, and that there is a best-fit relationship in terms of volume and function among different fat depots that needs to be met to maintain the systemic energy balance and to prevent the complications related to obesity.     

Distinct long-term regulation of glycerol and non-esterified fatty acid release by insulin and TNF-α in 3T3-L1 adipocytes

Aims/hypothesis. Adipose tissue lipolysis plays a central part in total body fuel metabolism. Our study was to assess the long-term regulation of glycerol and non-esterified fatty acid (NEFA) release by insulin or TNF-α.¶Methods. Fully differentiated 3T3-L1 adipocytes were exposed for up to 22 h to insulin or TNF-α.¶Results. Long-term insulin treatment resulted in increased basal glycerol release, reaching sixfold at 22 h with 1 nmol/l insulin. Partial inhibition was observed by pharmacologically inhibiting phosphatidylinositol 3-kinase or the mitogen-activated kinase kinase – extracellular signal-regulated kinase cascades. This represented 50–60 % of the response induced by 1 nmol/l TNF-α and approximately 40 % of the glycerol release maximally stimulated by isoproterenol (1 μmol/l, 30 min). The cellular mechanism seemed to be distinct from that of TNF-α: First, glycerol release in response to long-term insulin was progressive with time and did not display a lag-time characteristic of the effect of TNF-α. Second, pretreatment and co-treatment of the cells with troglitazone greatly inhibited TNF-α-induced glycerol release (128.5 ± 10.2 to 35.4 ± 2.1 nmol/mg protein per h) but not the effect of insulin, which was exaggerated. Third, hormone-sensitive lipase protein content was decreased (45 %) by TNF-α but not following long-term insulin. Finally, TNF-α was associated with NEFA release to the medium, whereas long-term insulin treatment was not. Moreover, glycerol release during isoproterenol-stimulated lipolysis was additive to the effect of long-term insulin, whereas NEFA release was inhibited by nearly 90 %.¶Conclusions interpretation. Contradictory to its short-term inhibitory effect, long-term insulin stimulates glycerol release with concomitant stimulation of NEFA re-esterification. [Diabetologia (2001) 44: 55–62]