defect in the activity of Delta6 and Delta5 desaturases

July 10, 2005

Prostaglandins Leukot Essent Fatty Acids. 2005 May;72(5):343-50.

A defect in the activity of Delta6 and Delta5 desaturases may be a factor predisposing to the development of insulin resistance syndrome.Das UN.UND Life Sciences, 1083 Main Street, Walpole, MA 02081, USA. undurti@...GLUT-4 (glucose transporter) receptor, tumor necrosis factor-alpha (TNF-alpha), interleukins-6 (IL-6), daf-genes and PPARs (peroxisomal proliferation activator receptors) play a role in the development of insulin resistance syndrome and associated conditions. But, the exact interaction between these molecules/factors and the mechanism(s) by which they produce insulin resistance syndrome is not clear. I propose that a defect in the activity of the enzymes Delta6 and Delta5 desaturases that are essential for the formation of long chain metabolites of essential fatty acids, linoleic acid and alpha-linolenic acid, is a factor in the development of insulin resistance syndrome. Long chain polyunsaturated fatty acids (LCPUFAs) increase cell membrane fluidity and enhance the number of insulin receptors and the affinity of insulin to its receptors; suppress TNF-alpha, IL-6, macrophage migration inhibitory factor (MIF) and leptin synthesis; increase the number of GLUT-4 receptors, serve as endogenous ligands of PPARs, modify lipolysis, and regulate the balance between pro- and anti-oxidants, and thus, play a critical role in the pathogenesis of insulin resistance. In the nematode, Caenorhabditis elegans, the protein encoded by daf-2 is 35% identical to the human insulin receptor; daf-7 codes a transforming growth factor-beta (TGF-beta) type signal and daf-16 enhances superoxide dismutase (SOD) expression. Melatonin has anti-oxidant actions similar to daf-16, TGF-beta and SOD. Calorie restriction enhances the activity of Delta6 and Delta5 desaturases, melatonin production, decreases daf-2 signaling, free radical generation, and augments anti-oxidant defenses that may explain the beneficial effect of diet control in the management of obesity, insulin resistance, and type II diabetes mellitus. These evidences suggest that the activities of Delta6 and Delta5 enzymes play a critical role in the expression and regulation of GLUT-4, TNF-alpha, IL-6, MIF, daf-genes, melatonin, and leptin by modulating the synthesis and tissue concentrations of LCPUFAs. Caloric restriction delays ageing by activating Sir 2 deacetylase in yeast, and expression of Sir 2 (SIRT1) in human cells. Both insulin and insulin-like growth factor-1 (IGF-1) attenuated this response. SIRT1 sequesters the proapoptotic factor Bax, prevents stress-induced apoptosis of cells, and thus, prolongs survival. In addition, SIRT1 repressed PPAR-gamma, and overexpression of SIRT1 attenuated adipogenesis, and upregulation of SIRT in differentiated fat cells triggered lipolysis and loss of fat, events that are known to attenuate insulin resistance and prolong life span. It remains to be seen whether LCPUFAs have a regulatory role in SIRT1 expression and control Sir 2 deacetylase activity. Thus, calorie restriction or reduced food intake has a role not only in the pathobiology of insulin resistance, but also in other associated conditions such as obesity, type II diabetes mellitus, ageing, and longevity.PMID: 15850715

July 10, 2005

> Prostaglandins Leukot Essent Fatty Acids. 2005 May;72(5):343-

50.

>

> A defect in the activity of Delta6 and Delta5 desaturases may be a

factor predisposing to the development of insulin resistance syndrome.

>

> Das UN.

>

> UND Life Sciences, 1083 Main Street, Walpole, MA 02081, USA.

undurti@h...

This guy I am sure has accumulated an extensive knowledge base

regarding these enzymes, their associated substrates, and the

biological activity profile of their products, but, I wonder if his

emphasis is as well-placed as he hopes.

I must admit that I am extremely " biased " against theories that draw

support from " membrane fluidity " associated theories of aging. This

type of reasoning is like thinking that drinking tiger's blood is going

to make you more ferocious (in bed....[rimshot])

I think the biophysical properties of most biological structures are

regulated within a very tight range, and although I will concede that

there are dietary means of manipulating certain variables, I do not

acknowledge the significance of " membrane fluidity " as of yet. I don't

see the utility of this variable.

In any case, where this guy may be " right " is in regards to

the " signalling " properties one could ascribe to LCPUFAs and " vegetable-

derived " metabolites. Such metabolites could very easily enter into

the " metabolic integration " that the bodies cells will perform to

determine how " anabolic " to " go " at any given time. In my own personal

take on the matter, I am of the opinion (never humble) that " saturated

fats " potentiate anabolism, while vegetable fats tend to " antagonize "

anabolism. You can go chasing all of the hormones (insulin, leptin,

TNF-alpha) that are associated with " anabolism " , but for discussion's

sake, I think the general principle is somewhat valid.

However, as of yet, attempts to produce significant changes in

the " aging process " itself through dietary manipulation of fats have

not met with anything approximating resounding success when approached

through metrics of " peroxideability " of " fluidity " . However, there was

an interesting finding back in 1991 with an increased mean survival

time with alpha-linolenate.

Peruse some of the following literature which pertains to my

opinionated stance above. The first paper is a guy who believes in

that whole " membrane " based theory of aging. Notice that the guys who

believe this type of thing publish as " lone wolves " . Below that are

some real experimentally-derived determinations that " fat manipulation "

does seem to do " as much " as you might predict from the

more " aggressively " fat-centric theory base. The most disturbing piece

of literature is the study from Japan [ PMID: 12808283 ]

that features 5 different feeding conditions in regards to fat

composition, with no difference in lipofuscin accumulation. In my

eyes, admittedly hubris-laden, that would seem to indicate that the

variable of " lifespan " is not easily accessible to dietary fat

manipulation in lower organisms.

=--==-=-=-=-=--=

J Theor Biol. 2005 May 21;234(2):277-88. Epub 2005 Jan 24.

\

V

" The membrane pacemaker theory of aging is an extension of the

oxidative stress theory of aging. It emphasises variation in the

fatty acid composition of membranes as an important influence on

lipid peroxidation and consequently on the rate of aging and

determination of lifespan......Lifespan extension by

calorie-restriction can also be explained by changes in membrane

fatty acid composition which result in membranes more resistant to

peroxidation. It is suggested that lifespan extension by reduced

insulin/IGF signalling may also be mediated by changes in membrane

fatty acid composition. " - PMID: 15757684

http://tinyurl.com/4ezx7

=====--=-=-=-=-=-

Biol Pharm Bull. 2003 Jun;26(6):766-70.

\

V

" The DHA/Soy and Per groups had decreased serum cholesterol levels

compared with the Lar and Saf groups, but the difference between the

Lar and Saf groups was not significant. The

3-hydroxy-3-methyglutary-CoA (HMG-CoA) reductase activity in the

liver was also significantly lower in the Per and DHA/Soy groups.

However, no significant difference in lipofuscin contents in the

brain and liver was observed among the 5 dietary groups, despite

significant differences in peroxidizability indices of the dietary

and/or tissue lipids. These results indicate that n-3 fatty acid-rich

oils are hypocholesterolemic by suppressing hepatic HMG-CoA reductase

activity compared with animal fats and high-linoleic (n-6) oil, but

tissue lipofuscin contents are not affected by a long-term feeding of

fats and oils with different degree of unsaturation in mice. " - PMID:

12808283

http://www.jstage.jst.go.jp/article/bpb/26/6/766/_pdf

=---==-=-=-=--==-=-=-

Exp Gerontol. 2004 Aug;39(8):1189-98.

\

V

" This study was designed to investigate the possible effect on DNA

double-strand breaks, antioxidant capacity and blood lipids of

feeding rats lifelong with two different dietary fat sources: virgin

olive oil (rich in the monounsaturated oleic acid) or sunflower oil

(rich in the polyunsaturated linoleic acid). No changes in mean or

maximal lifespan were observed. " - PMID: 15288693

http://tinyurl.com/b3l36

=-=-=-=-=-=-=-==-

J Gerontol. 1991 Jan;46(1):B17-22

\

V

" An alpha-linolenate-rich diet with a peroxidizability index (PI) of

142 and a linoleate-rich diet with a PI value of 80 were used.

Long-term feeding of these diets induced a significant difference in

the n-3/n-6 ratios of highly unsaturated fatty acids in brain, but

the PI values and the conjugated diene contents were similar between

the two dietary groups. Rats fed the alpha-linolenate-rich diet had a

longer mean survival time and an increased learning ability in

senescence. These results contradict an autoxidation-related lipid

peroxide theory of aging, and indicate that the aging process must

also be considered in terms of n-3/n-6 balance of dietary fats. " -

PMID: 1670780

http://tinyurl.com/czypk

=-=-=-=-=-=-=-=-=-=-

T.

pct35768@...

July 10, 2005

--- In , " jwwright " <jwwright@e...>

wrote:

> Prostaglandins Leukot Essent Fatty Acids. 2005 May;72(5):343-

50.

>

> A defect in the activity of Delta6 and Delta5 desaturases may be a

factor predisposing to the development of insulin resistance syndrome.

>

> Das UN.

>

> UND Life Sciences, 1083 Main Street, Walpole, MA 02081, USA.

undurti@h...

[ Hopefully this has better formatting...... ]

This guy I am sure has accumulated an extensive knowledge base

regarding these enzymes, their associated substrates, and the

biological activity profile of their products, but, I wonder if his

emphasis is as well-placed as he hopes.

I must admit that I am extremely " biased " against theories that draw

support from " membrane fluidity " associated theories of aging. This

type of reasoning is like thinking that drinking tiger's blood is

going to make you more ferocious (in bed....[rimshot])

I think the biophysical properties of most biological structures are

regulated within a very tight range, and although I will concede that

there are dietary means of manipulating certain variables, I do not

acknowledge the significance of " membrane fluidity " as of yet. I

don't see the utility of this variable.

In any case, where this guy may be " right " is in regards to

the " signalling " properties one could ascribe to LCPUFAs

and " vegetable-derived " metabolites. Such metabolites could very

easily enter into the " metabolic integration " that the bodies cells

will perform to determine how " anabolic " to " go " at any given time.

In my own personal take on the matter, I am of the opinion (never

humble) that " saturated fats " potentiate anabolism, while vegetable

fats tend to " antagonize " anabolism. You can go chasing all of the

hormones (insulin, leptin, TNF-alpha) that are associated

with " anabolism " , but for discussion's sake, I think the general

principle is somewhat valid.

However, as of yet, attempts to produce significant changes in

the " aging process " itself through dietary manipulation of fats have

not met with anything approximating resounding success when

approached through metrics of " peroxideability " of " fluidity " .

However, there was an interesting finding back in 1991 with an

increased mean survival time with alpha-linolenate.

Peruse some of the following literature which pertains to my

opinionated stance above. The first paper is a guy who believes in

that whole " membrane " based theory of aging. Notice that the guys who

believe this type of thing publish as " lone wolves " . Below that are

some real experimentally-derived determinations that " fat

manipulation " does seem to do " as much " as you might predict from the

more " aggressively " fat-centric theory base. The most disturbing

piece of literature is the study from Japan [ PMID: 12808283 ]