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“To kill an error is as good a service as, and sometimes even better than, the establishing of a new truth or fact”
~ Charles Darwin (it's evolutionary baybeee!)

Wednesday, June 9, 2010

ASP activates Glucose transport in Human Adipocytes

ASP stimulates glucose transport in cultured human adipocytes  (Full Text PDF)


Introduction
Acylation Stimulating Protein (ASP) is the most potent stimulant of triglyceride synthesis in human adipocytes yet described.1 The rate at which triglycerides are cleared from the plasma appears to be related not only to the functional activity of LPL but also to the capacity of peripheral tissues to store fatty acid as intracellular triglycerides. The ability of ASP to regulate this process may, therefore, be of physiological importance.2,3 As human adipocytes differentiate, they become competent to synthesize and secrete the three proteins necessary to generate ASP. These are the third component of complement (C3), factor B, and adipsin.4 The capacity to produce ASP appears relatively late in differentiation but before the sharp increase in the capacity of adipocytes to synthesize triglyceride.5 Subsequently, the mass of triglycerides within adipocytes, the rate at which they synthesize triglycerides, and their capacity to generate ASP are closely correlated.4,5 Moreover, as they differentiate, not only do human adipocytes generate more ASP,  they become much more responsive to ASP.4 
The mechanisms by which ASP increases triglyceride synthesis are under intensive study. Interaction with an apparent membrane receptor appears to be critical6 and studies of the cell signalling mechanism point to activation of a protein kinase C pathway.7  ASP increases triglyceride synthesis by two coordinate mechanisms. One is to increase the activity of diacylglycerol acyltransferase, the enzyme which controls the last step in the synthesis of a triglyceride molecule.8 The other is to increase specific membrane transport of glucose through specific effects on translocation of glucose transporters. This second effect of ASP has only been demonstrated in human skin fibroblasts and recently in L6 myotubes.9,10 The purpose of the present study was to determine if ASP produced this effect in human adipocytes, a physiologically important tissue in glucose homeostasis, and to compare its potency to that of insulin.
Discussion
The data from the present study demonstrates: 
(1) that ASP stimulates specific membrane transport of glucose in human preadipocytes and adipocytes in a time and concentration dependent manner
(2) that differentiated adipocytes are more responsive to ASP than preadipocytes
(3) that ASP is as potent as insulin in inducing specific membrane transport of glucose in adipocytes.
These data extend our knowledge as to the mechanisms by which ASP causes triglyceride synthesis to increase in human adipocytes. Our previous work focused primarily on triglyceride synthesis.   Experimental data demonstrated that both omental and subcutaneous adipose tissue (primary adipocytes or cultured adipocytes) are responsive to ASP13,14  although the stimulation is greater in subcutaneous tissue suggesting regional specificity.13
The physiological significance of these effects is becoming increasingly apparent. Until recently, triglyceride clearance from plasma was thought to be determined exclusively by lipoprotein lipase activity, greater triglyceridehydrolytic capacity resulting in more rapid removal of triglyceride from plasma.15,16  However, the correlation between lipoprotein lipase activity and triglyceride clearance is poor17,18 and studies have shown that, in fact, lipoprotein lipase would appear to be present in excess.15 There is direct evidence in humans that the rate of fatty acid uptake from triglyceride-rich particles is limited.19 A major portion of the fatty acids released from chylomicrons are not immediately taken up by adipocytes20 but rather continue to circulate. Thus, the rate of chylomicron triglyceride hydrolysis by lipoprotein lipase is not a direct function of the mass of this enzyme present on the endothelial surface, but the increase in ambient circulating fatty acids can also result in product inhibition of lipoprotein lipase and influence triglyceride clearance.19,21±23
Our hypothesis has been that adipocyte triglyceride synthesis determines the rate at which fatty acids are taken up by adipocytes from the adjacent capillary space. This rate will influence the proportion of fatty acids which enter adipocytes directly after lipolysis as opposed to the proportion which exit the adipocyte capillary space and pass within the circulation to the liver. A decreased rate of adipocyte fatty acid uptake results in increased delivery of fatty acids to the liver and subsequently, increased VLDL production.24 Any factor which increases the rate of fatty acid uptake and triglyceride synthesis will enhance the efficiency of adipocyte triglyceride storage. Normal plasma ASP in a group of healthy control subjects (35±65) is 32.0 2.6 nM.25 Plasma ASP increases postprandially 26 up to two-fold and is a potent in vitro stimulator of triglyceride synthesis in human adipocytes4 and may thus enhance adipose tissue efficiency.
However, fatty acids are not the only building block required for triglyceride synthesis and storage. Glucose is the source of the glycerol-3-phosphate backbone, and it is well known that glucose transport increases postprandially in response to hormone stimuli.27,28 The present study adds importantly to the documentation of this pathway in humans. That ASP causes specific membrane transport of glucose to increase in adipocytes is clear, although we have not in this instance directly demonstrated the mechanism responsible for this effect.  Based on our previous results in cultured human skin fibroblasts and L6 myotubes, ASP likely induces translocation of glucose transporters.9,10 In the fibroblast model, ASP induced translocation of glut-1 transporters to the cell membrane whereas in the L6 myotube model, ASP stimulates translocation of glut-1, glut-3 and glut-4 transporters, all to the same extent as insulin. As well, the fact that lower ASP concentrations are more effective at increasing glucose transport in the differentiated adipocytes is consistent with our previous observation that the effects of ASP on triglyceride synthesis become more pronounced during the process of adipocyte differentiation.4 Although higher concentrations of ASP were necessary to achieve the same stimulation as insulin, it should be noted that the physiological levels of plasma ASP are also higher than insulin: 32.0 2.6nMASP25 vs 36±180pM insulin.29 The effects of ASP and insulin on glucose transport were not additive in the differentiated adipocytes whereas they are in human skin fibroblast and the L6 myotube models.9,10 This difference may be consequent to the differentiation induced changes in the level of expression of the various glucose transporters.  In the preadipocytes, although there was a trend towards additivity of the ASP and insulin effects, because the insulin effect (although significant) was modest, this was difficult to assess. Nevertheless, demonstration that ASP directly induces specific membrane transport of glucose is critical to documenting the mechanisms by which it increases triglyceride synthesis in adipocytes.

What I get from this is:  Insulin is not required for glucose to be transported into fat cells, knocking another leg out from under the whole insulin fat dysregulation theory.

4 comments:

MM said...

If insulin is really not required to store glucose as fat then why do type 1 diabetics who make no, or very little insulin lose weight like crazy, and can't gain weight until they're put in insulin shots?

CarbSane said...

Insulin's main action in adipose tissue is to suppress lipolysis/release, which is why both forms of diabetes, Type 1 = absence of insulin, Type 2 = resistance to the actions of insulin, are characterized by elevated NEFA (free fatty acids). The Trig/FA cycle is crucial for life and occurs even during starvation. Untreated T1's would probably die even more quickly if they didn't have at least a marginally functional Trig/FA cycle. Unfortunately their equilibrium leaves way too many NEFA/FFA out in circulation where it may get stored in other tissues and do damage. Drugs that block glyceroneogenesis cause weight loss and/or reduced weight gain as well.

Nigel Kinbrum said...

MM, people with insufficient insulin wee out loads of calories as glucose (& ketones) due to uncontrolled glucogenesis & ketogenesis. I suppose you could call that a "Metabolic Advantage" if it wasn't for the fact that it usually proves fatal.

See also Insulin: An Undeserved Bad Reputation, Part 4: The Biggest Insulin Myth of Them All

James Krieger said...

To add to CarbSane's comment, insulin also helps prevent runaway lipolysis and proteolysis. Without insulin, you have massive lipolysis and proteolysis (and the high rate of gluconeogenesis from the protein breakdown), meaning the person starts to lose massive amounts of both lean and fat tissue. This is why someone without insulin loses weight like crazy.

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