It has been shown that the antilipolytic effect of insulin is stronger in sc than in visceral fat As the visceral fat depot is in direct contact with the liver through the portal circulation, the inability of insulin to decrease lipolysis in visceral fat cells may result in a higher FFA flux to the liver and consequently VLDL overproduction, leading to dyslipidemia.
Supporting this concept, a recent study has shown that low and physiological increased insulin concentrations suppress lipolysis in skeletal muscle We cannot rule out that some of the results obtained in the present study reflect insulin and catecholamine effects on skeletal muscle.
During the second rest period after placebo, when heart rate and insulin concentrations were low, FFA declined to basal levels 0 min. However, although after glucose, heart rate and insulin concentrations decreased, FFA concentrations remained below basal concentrations.
This could be explained by a prolonged action of plasma insulin on the suppression of HSL. Further research will be necessary to investigate the duration of suppression of HSL by insulin after a decrease in plasma insulin concentrations.
In conclusion, in this study we have demonstrated that the catecholamine-induced HSL activation can be overruled by insulin-mediated inhibition in healthy, insulin-sensitive volunteers. Furthermore, the suppression of FFA by insulin under physiological conditions is positively associated with fasting plasma insulin concentrations.
This noninvasive in vivo test may be used in patients to test the antilipolytic action of insulin, HSL stimulation, and suppression of HSL activation by insulin under different conditions.
Future studies will investigate whether different patient groups with differences in insulin sensitivity will show similar results concerning HSL regulation by insulin and catecholamines in vivo. Frayn KN Non-esterified fatty acid metabolism and postprandial lipaemia. Google Scholar. Int J Obes 9 : — Hahn P The postnatal development of hormone sensitive lipase in brown and white adipose tissue of the rat.
Experientia 21 : — J Clin Endocrinol Metab 83 : — Engfeldt P , Hellmer J , Wahrenberg H , Arner P Effects of insulin on adrenoceptor binding and the rate of catecholamine-induced lipolysis in isolated human fat cells.
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J Clin Endocrinol Metab 64 : 17 — J Clin Endocrinol Metab 84 : — Diabetologia 42 : — Oxford University Press is a department of the University of Oxford. It furthers the University's objective of excellence in research, scholarship, and education by publishing worldwide.
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Search ADS. Google Scholar PubMed. The postnatal development of hormone sensitive lipase in brown and white adipose tissue of the rat.
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Adipose tissue lipoprotein lipase and hormone-sensitive lipase. Regulation of fatty acid movement in human adipose tissue in the postabsorptive-to-postprandial transition. Coordinated regulation of hormone-sensitive lipase and lipoprotein lipase in human adipose tissue in vivo: implications for the control of fat storage and fat mobilization. Proteolysis of human apolipoprotein B: effect on quantitative immunoturbidimetry.
Insulin resistance, lipid and fatty acid concentrations in healthy Europeans. Effects of cortisol and growth hormone on lipolysis in human adipose tissue. Resistance to insulin suppression of plasma free fatty acid concentrations and insulin stimulation of glucose uptake in non-insulin- dependent diabetes mellitus.
Subcutaneous adipose tissue metabolism at menopause: importance of body fatness and regional fat distribution. Effects of an oral and intravenous fat load on adipose tissue and forearm lipid metabolism. Biochemical quantification of sympathetic nervous activity in humans using radiotracer methodology: fallibility of plasma noradrenaline measurements.
Norepinephrine spillover in forearm and subcutaneous adipose tissue before and after eating [published erratum appears in J Clin Endocrinol Metab Dec;84 12 ].
Regional difference in insulin inhibition of non-esterified fatty acid release from human adipocytes: relation to insulin receptor phosphorylation and intracellular signalling through the insulin receptor substrate-1 pathway.
Lipolysis in skeletal muscle is rapidly regulated by low physiological doses of insulin. Issue Section:. Download all slides. View Metrics. Email alerts Article activity alert. Advance article alerts. New issue alert. Receive exclusive offers and updates from Oxford Academic. Related articles in Google Scholar. Citing articles via Google Scholar.
Basal lipolytic activity was higher in adipose explants from dry compared with fresh Fig. In adipose samples taken at lactation, basal lipolytic activity was numerically increased compared with those taken at fresh Fig.
Independent of the period, explants with larger adipocytes demonstrated higher basal lipolytic activity Fig. Inhibition of basal lipolytic activity by CAY was minimal at dry Fig. In fresh and lactation, CAY inhibited basal lipolysis by Glycerol release and the effect of adipocyte volume during inhibition of HSL activity. P -values for the effect of period and adipocyte size volume in pL on the different variables are derived from the linear mixed effect model.
The beta-adrenergic agonist ISO stimulated the lipolytic activity of adipose explants in all periods in a similar way Fig. Compared with basal lipolysis, ISO increased lipolysis 5- to fold Fig. The inhibition of stimulated lipolytic activity by CAY was more pronounced in larger adipocytes Fig. Inhibition of stimulated lipolysis by insulin was more marked in dry compared with fresh for both insulin doses Fig.
Adipocyte size did not influence the inhibitory effect of insulin. Expression of the lipolytic gene network was paradoxically reduced during the peak of FA mobilization postpartum. The expression of LPL was decreased pronouncedly in fresh and lactation compared to dry Table 1.
Similarly, the lipogenic gene network was downregulated after parturition fresh and lactation. Higher expression of DGAT2 was associated with larger adipocytes in adipose samples at fresh and lactation samples but not in the dry samples Fig.
The expression of two genes encoding important proteins from the gene network involving the metabolism of glucose, SLC2A4 formerly known as GLUT4 or glucose transporter 4 and PGK1, were decreased in fresh and lactation compared with the dry sample Table 1.
P -values for the effect of period on the ratio of protein phosphorylation and the change in ratio of protein phosphorylation are derived from the linear mixed effect model. The effect of insulin on the activation of AKT was more pronounced in the dry and lactation period compared with the fresh period Fig.
Mobilization of FA reserves from AT supports energy deficits generated by rapid fetal growth and lactation during the periparturient period. In the present study, net FA release from adipocytes into circulation was reflected by an increase in plasma BHB and FFA concentrations, a reduction in the diameter and volume of adipocytes, and an increase in adipocyte number per g of tissue Our results demonstrate that the level of basal lipolytic activity in SCAT is dynamic throughout the periparturient period and decreases in the fresh compared with the dry period.
Similarly, Kokkonen, et al. Other studies reported that basal lipolysis did not increase substantially after calving 30 , As lactation progresses, this inhibitory effect declines due to reductions in blood BHB concentrations. Additionally, results from the present study indicate that the postpartum peak in circulating FFA may be related to the drastic reduction in the lipogenesis process, that includes re-esterification of FFA, rather than an increase in lipolysis Although AT explant lipogenic activity was not measured in the present study, the mRNA expression of the lipogenic network decreased after parturition supporting our hypothesis.
It is important to note that the present study did not evaluate basal lipolysis in visceral AT. Thus it is possible that, given the substantial differences in lipolytic activity between adipocytes from different depots 9 , 34 , circulating FFA could be derived from internal adipose depots rather than SCAT.
As far as the authors are aware, this is the first study using pharmacological inhibition of HSL in explants from dairy cattle.
In the fresh and lactation periods, nearly half of the basal lipolysis was attributable to HSL activity. These observations are in agreement with the increased rate of HSL phosphorylation in the postpartum period despite a decrease in total HSL protein content 20 , It is known that basal lipolysis is related to adipocyte size 9 , 38 and regulated by ATGL activity 39 , In most studies, ATGL protein content or gene expression remain unchanged or downregulated in early lactation and are independent of energy balance status 40 , 42 , In our study, this was reflected by the decrease in ATGL dependent basal lipolytic activity i.
In agreement with Koltes and Spurlock 40 , this finding reflects a shift from ATGL dependent basal lipolysis during positive energy balance dry period to HSL dependent basal lipolysis during negative energy balance fresh and lactation period. The increase in HSL activity postpartum is caused by different mechanisms including decreased insulin concentrations, potential decreased insulin signaling in adipocytes, increased growth hormone concentrations, and increased catecholamine sensitivity of the adipocytes 7 , 44 , Based on these observations, we suggest that ATGL determines a certain level of basal lipolytic activity that is directly related to adipocyte size.
HSL modulates the level of lipolysis based on the individual requirements of each animal Future studies inhibiting ATGL activity may elucidate the role of this lipase in modulating basal lipolysis in dairy cows. This finding is in contrast with the observation that lipolytic responses of adipocytes to catecholamines is increased in the postpartum period Based on our calculations of the contribution of HSL to both basal and demand lipolysis, we propose that higher basal HSL activity i.
Insulin is the most potent physiological inhibitor of lipolysis in AT Since insulin exerts an inhibitory effect on stimulated lipolysis, by decreasing HSL phosphorylation, it was necessary to determine the effect of insulin after ISO treatment Inhibition of ISO stumulated lipolysis by both doses of insulin was less pronounced in the fresh period compared with the dry period.
These observations indicate that during the fresh period adipocytes exhibit limited sensitivity to the anti-lipolytic actions of insulin. This insulin resistant state appears to be limited in time since the anti-lipolytic effect of insulin increased during the lactation period. Similar observations were reported by Ji, et al. Insulin signaling in adipose samples taken during intravenous glucose tolerance tests was lower in the postpartum period compared with the prepartum period 20 , However, it is important to clarify that insulin concentrations during intravenous glucose tolerance tests are usually supra-physiological and typically a reduction in insulin secretion is observed in the postpartum period.
This is the first study to demonstrate an insulin resistant state in adipocytes from cows during the first week of lactation fresh using physiologically relevant insulin concentrations. In the immediate postpartum period, minimal lipolysis inhibition and reduced lipogenesis stimulation driven by low insulin concentrations and reduced sensitivity to the anti-lipolytic effects of insulin increase the net release of FA into circulation. Insulin resistance during the first 2 weeks after parturition might support a sufficient FA release from AT while adipocytes adapt their metabolism to the intense energy requirements of lactation.
However, AT insulin resistance in the immediate postpartum period may have a detrimental impact on health and productivity of dairy cows because it promotes excessive lipolysis Further research is needed to determine the physiological and pathological consequences of periparturient adipocyte insulin resistance. Insulin inhibits lipolytic activity by decreasing the phosphorylation and thus activity of HSL. In vitro studies using adipocyte cell lines demonstrated that, depending on the metabolic environment, the anti-lipolytic effect of insulin occurs via an AKT-dependent or an AKT-independent pathway.
We conclude that since ISO stimulated lipolysis was not affected by time relative to parturition, the anti-lipolytic effect of insulin is directly related to a state of insulin resistance in the adipocyte. Given that insulin only inhibits lipolysis through the reduction of HSL phosphorylation, it would not be possible to determine the inhibitory effect of insulin on basal lipolysis at dry when HSL activity was minimal i. Hence it is necessary to standardize the lipolytic stimulus before insulin responses can be assessed in vitro explants.
Accordingly, in the present study, total HSL protein expression was lower in the fresh period compared with the dry and lactation periods. And other studies have demonstrated that AT lipolysis is mainly regulated by posttranslational control mechanisms, i. The decreased protein expression of HSL is accompanied by an increase in the ratio of phosphorylated HSL in the fresh period, indicating an increased lipolytic activity of HSL Basal glycerol release was influenced by adipocyte size.
Larger adipocytes had higher basal lipolytic activity compared with smaller adipocytes independent of the period when the samples were collected. The imbalance between the lipolysis and lipogenesis in larger adipocytes favoring lipolytic activity in the basal state may provide an explanation why over-conditioned cows, which have larger adipocytes 9 , are at increased risk of having higher concentrations of circulating FFA and BHB during the periparturient period 59 , Remarkably, the anti-lipolytic effect of insulin was not influenced by adipocyte size as previously shown in over-conditioned cows 9 which indicates that stimulated lipolysis in adipocytes from over-conditioned cows is not insulin resistant.
More research is needed to substantiate the effect of lipogenic enzymes in the postpartum period and to determine the potential effect of modulating lipogenic activity on FA mobilization from AT. Despite being lipolytic, LPL is responsible for the provision of FA to the adipocytes by breaking down circulating triacylglycerol in the capillaries of AT The activity of lipogenic enzymes is controlled by transcriptional mechanisms and affected by the availability of energy 11 , Negative energy balance at the beginning of lactation leads to a pronounced decrease in the expression and activity of genes encoding proteins of the de-novo lipogenic, and glycerolphosphate pathways 7 , 11 , Reduced lipogenic activity in AT may contribute to the increase in circulating FFA levels in the immediate postpartum period More research is warranted to determine the impact of modulating lipogenic enzyme activity on FA release from AT in the periparturient period of dairy cows.
The decreased expression of genes for glucose metabolism, GLUT4 , and PGK1 , in the postpartum period, is in agreement with the homeorhetic mechanisms that preserve glucose for milk production.
In the postpartum period, lower PGK1 will lead to lower glycolysis within adipocytes. And at the same time, downregulation of GLUT4 expression leads to lower insulin-dependent glucose uptake in the adipocytes 11 , GLUT4 expression was specially reduced in large adipocytes during the dry period.
This may indicate that the glucose metabolism of large adipocytes is less sensitive to insulin compared with small adipocytes prior to calving. Similarly, insulin sensitivity of glucose metabolism was negatively associated with fat accumulation in dairy cows at the end of the dry period These results provide further evidence of an insulin resistant state of glucose metabolism of adipocytes by excessive accumulation of triacylglycerol through a decreased expression of GLUT4.
AT lipolytic responses during the periparturient period are characterized by a shift from ATGL dependent basal lipolysis during positive energy balance dry period to HSL dependent basal lipolysis during negative energy balance fresh and lactation period. The decrease in basal lipolytic activity and a broadly decreased transcriptional regulation of the lipogenic gene network suggests that decreased lipogenesis is an important contributor to FA release from SCAT postpartum.
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