Re: n-3 n-6 lipids and glucose metabolism

[Guest guest]

Hi all,

Ever since I posted the studies which established a link between the

absence of diabetes and induced essential fatty acid defficiency in

rats with a bred strong succeptibility to diabetes, I have been

attentative as to whether research had come up with any possible

mechanism to account for the apparent endocrine disruptive aspects of

PUFA. The evidence contra PUFA in this regard seemed to center around

its pro-oxidative tendency. Thus the link, if any, was very indirect.

However, a strong acknowledged link does exist and is subject to much

research. It appears that PUFA strongly inhibit glucose metabolism

through a number of possible unelucidated(?) mechanisms. Does this

mean that high carbohyrate diets as such do not play the decisive role

in diabetes? This is very suggestive when one keeps in mind that the

diet of the average north-american is high in n-6 (though low in n-3).

Some samples of what is available:

The glycolytic enzyme, L-pyruvate kinase (L-PK), plays an important

role in hepatic glucose metabolism. Insulin and glucose induce L-PK

gene expression, while glucagon and polyunsaturated fatty acids (PUFA)

inhibit L-PK gene expression.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed & cmd=Retrieve & dopt=Abstra\

ctPlus & list_uids=10787435 & itool=iconfft & query_hl=1 & itool=pubmed_docsum

Some highlights of the full text:

Feeding rats either fish oil or the potent PPAR{alpha} activator,

WY14,643, suppressed rat hepatic L-PK mRNA and gene transcription.

L-PK gene expression is suppressed by diabetes, glucagon, and

polyunsaturated fatty acids [PUFA] (1) (2) (3) (4) (11) (12). Highly

unsaturated fatty acids like eicosapentaenoic acid (20:5, n;–3) are

particularly strong suppressors of L-PK gene expression (11) (12).

PUFA-regulated factors interfere with the glucose-mediated

transactivation of L-PK...

Another study, essentially same conclusions:

Carbohydrate regulatory element-binding protein (ChREBP), MAX-like

factor X (MLX), and hepatic nuclear factor-4alpha (HNF-4alpha) are key

transcription factors involved in the glucose-mediated induction of

hepatic L-type pyruvate kinase (L-PK) gene transcription. n-3

polyunsaturated fatty acids (PUFA) and WY14643 (peroxisome

proliferator-activated receptor alpha (PPARalpha) agonist) interfere

with glucose-stimulated L-PK gene transcription in vivo and in rat

primary hepatocytes. Feeding rats a diet containing n-3 PUFA or

WY14643 suppressed hepatic mRNA(L-PK)...

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed & cmd=Retrieve & dopt=Abstra\

ctPlus & list_uids=16644726 & query_hl=1 & itool=pubmed_docsum

Here again showing that the inclusion of PUFA in a high carb diet can

have immediate, very evident results:

Polyunsaturated fatty acids (PUFA) of the (n-6) and (n-3) families

inhibit the rate of gene transcription for a number of hepatic

lipogenic and glycolytic genes, e.g., fatty acid synthase (FAS). In

contrast, saturated and monounsaturated fatty acids have no inhibitory

capability. The suppression of gene transcription resulting from the

addition of PUFA to a high carbohydrate diet: occurs quickly (< 3 h)

after its addition to a high glucose diet; can be recreated with

hepatocytes cultured in a serum-free medium containing insulin and

glucocorticoids; can be demonstrated in diabetic rats fed fructose

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed & cmd=Retrieve & dopt=Abstra\

ctPlus & list_uids=9558724 & query_hl=1 & itool=pubmed_docsum

Dietary polyunsaturated fatty acids (PUFA) have profound effects on

hepatic gene transcription leading to significant changes in lipid

metabolism. PUFA rapidly suppress transcription of genes encoding

specific lipogenic and glycolytic enzymes and induce genes encoding

specific peroxisomal and cytochrome P450 (CYP) enzymes.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed & cmd=Retrieve & dopt=Abstra\

ctPlus & list_uids=10419152 & query_hl=1 & itool=pubmed_DocSum

In another earlier report:

L-type pyruvate kinase (L-PK) is a key glycolytic enzyme regulating

the flux of metabolites through the pyruvate-phosphoenolpyruvate cycle

(1). The regulation of L-PK is complex involving both hormones and

nutrients. We have found that feeding rats diets containing

polyunsaturated fatty acids (PUFA) significantly inhibits hepatic

pyruvate kinase enzyme activity (> 60%) and suppresses mRNAPK

abundance (> 70%). Studies with primary hepatocytes indicate that PUFA

act directly on hepatocytes. Specifically, arachidonic (20:4, omega 6)

and eicosapentaenoic (20:5, omega 3) acid suppressed both mRNAPK

llevels and the activity of a transfected PKCAT (-4300/+12) fusion

gene by > 70%. This is due to an inhibition of the

insulin/glucose-mediated transactivation of L-PKCAT.

What sense doe we make of all this?

>

> http://snipurl.com/wd9e

>

> Inhibition of inflammatory response in transgenic fat-1 mice on a

> calorie-restricted diet.

>

> * Bhattacharya A,

> * Chandrasekar B,

> * Rahman MM,

> * Banu J,

> * Kang JX,

> * Fernandes G.

>

> Department of Medicine, Division of Clinical Immunology and

> Rheumatology, University of Texas Health Science Center, San ,

> TX 78229, USA.

>

> Both n-3 fatty acids (n-3 FA) and calorie-restriction (CR) exert

> anti-inflammatory effects in animal models of autoimmunity and

> inflammation. In the present study we investigated the synergistic

> anti-inflammatory effects of n-3 FA and CR on LPS-mediated

> inflammatory responses using fat-1 transgenic mice that generate n-3

> FA endogenously. Wild-type (WT) and fat-1 mice were maintained on ad

> libitum (AL) or CR (40% less than AL) diet for 5 mo; splenocytes were

> cultured in vitro with/without LPS. Our results show: (i) no

> difference in body weights between WT and fat-1 mice on AL or CR

> diets, (ii) lower n-6/n-3 FA ratio in splenocytes from fat-1 mice on

> both AL and CR diets, (iii) significant reduction in NF-kappaB

> (p65/p50) and AP-1 (c-Fos/c-Jun) DNA-binding activities in splenocytes

> from fat-1/CR mice following LPS treatment, and (iv) significant

> reduction in kappaB- and AP-1-responsive IL-6 and TNF-alpha secretion

> following LPS treatment in splenocytes from fat-1/CR mice. The

> inhibition of LPS-mediated effects was more pronounced in fat-1/CR

> mice when compared to fat-1/AL or WT/CR mice. These data show that

> transgenic expression of fat-1 results in decreased pro-inflammatory

> n-6 FA, and demonstrate for the first time that splenocytes from fat-1

> mice on CR diet exhibit reduced pro-inflammatory response when

> challenged with LPS. These results suggest that n-3 lipids with

> moderate CR may confer protection in autoimmune and inflammatory

diseases.

>

> PMID: 16962071

>

[Guest guest]

Well , since you ask: " What sense do we make of all this? " ,

here is an answer: I don't have a clue, because I don't understand

it. For example, here are two passages:

A:

> Dietary polyunsaturated fatty acids (PUFA) have profound effects on

> hepatic gene transcription leading to significant changes in lipid

> metabolism. PUFA rapidly suppress transcription of genes encoding

> specific lipogenic and glycolytic enzymes and induce genes encoding

> specific peroxisomal and cytochrome P450 (CYP) enzymes.

B:

> In contrast, saturated and monounsaturated fatty acids have no

> inhibitory capability. The suppression of gene transcription

> resulting from the addition of PUFA to a high carbohydrate diet:

> occurs quickly (< 3 h) after its addition to a high glucose diet;

> can be recreated with hepatocytes cultured in a serum-free medium

> containing insulin and glucocorticoids; (and) can be demonstrated

> in diabetic rats fed fructose.

So, using non-technical terminology, I have a question: Are the

effects described in A) and above 'good' or 'bad'? Knowing the

answer to that would help me a lot.

Whatever the answer, we do know that the Nurses' Health Study (NHS)

found appreciably lower incidence of cardiovascular problems among

those who consumed the most PUFA, compared with those eating less of

it and more of other types of fat. Of course as previously noted, I

prefer empirical studies, like the NHS, because they look at what

actually happens to real people in the real world.

So my SUSPICION is that the effects described in A) and above may

be beneficial. But that is purely an attempt to draw inferences from

far from closely connected information.

And, of course, for those trying to restrict their caloric intake it

seems to make little sense to overdo fat of any kind.

Rodney.

>

> Hi all,

>

> Ever since I posted the studies which established a link between the

> absence of diabetes and induced essential fatty acid defficiency in

> rats with a bred strong succeptibility to diabetes, I have been

> attentative as to whether research had come up with any possible

> mechanism to account for the apparent endocrine disruptive aspects

of

> PUFA. The evidence contra PUFA in this regard seemed to center

around

> its pro-oxidative tendency. Thus the link, if any, was very

indirect.

>

> However, a strong acknowledged link does exist and is subject to

much

> research. It appears that PUFA strongly inhibit glucose metabolism

> through a number of possible unelucidated(?) mechanisms. Does this

> mean that high carbohyrate diets as such do not play the decisive

role

> in diabetes? This is very suggestive when one keeps in mind that the

> diet of the average north-american is high in n-6 (though low in n-

3).

>

>

> Some samples of what is available:

>

>

> The glycolytic enzyme, L-pyruvate kinase (L-PK), plays an important

> role in hepatic glucose metabolism. Insulin and glucose induce L-PK

> gene expression, while glucagon and polyunsaturated fatty acids

(PUFA)

> inhibit L-PK gene expression.

>

> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?

db=pubmed & cmd=Retrieve & dopt=AbstractPlus & list_uids=10787435 & itool=icon

fft & query_hl=1 & itool=pubmed_docsum

>

>

> Some highlights of the full text:

>

> Feeding rats either fish oil or the potent PPAR{alpha} activator,

> WY14,643, suppressed rat hepatic L-PK mRNA and gene transcription.

>

>

> L-PK gene expression is suppressed by diabetes, glucagon, and

> polyunsaturated fatty acids [PUFA] (1) (2) (3) (4) (11) (12). Highly

> unsaturated fatty acids like eicosapentaenoic acid (20:5, n;–3) are

> particularly strong suppressors of L-PK gene expression (11) (12).

> PUFA-regulated factors interfere with the glucose-mediated

> transactivation of L-PK...

>

> Another study, essentially same conclusions:

>

> Carbohydrate regulatory element-binding protein (ChREBP), MAX-like

> factor X (MLX), and hepatic nuclear factor-4alpha (HNF-4alpha) are

key

> transcription factors involved in the glucose-mediated induction of

> hepatic L-type pyruvate kinase (L-PK) gene transcription. n-3

> polyunsaturated fatty acids (PUFA) and WY14643 (peroxisome

> proliferator-activated receptor alpha (PPARalpha) agonist) interfere

> with glucose-stimulated L-PK gene transcription in vivo and in rat

> primary hepatocytes. Feeding rats a diet containing n-3 PUFA or

> WY14643 suppressed hepatic mRNA(L-PK)...

>

>

> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?

db=pubmed & cmd=Retrieve & dopt=AbstractPlus & list_uids=16644726 & query_hl=1

& itool=pubmed_docsum

>

>

> Here again showing that the inclusion of PUFA in a high carb diet

can

> have immediate, very evident results:

>

> Polyunsaturated fatty acids (PUFA) of the (n-6) and (n-3) families

> inhibit the rate of gene transcription for a number of hepatic

> lipogenic and glycolytic genes, e.g., fatty acid synthase (FAS). In

> contrast, saturated and monounsaturated fatty acids have no

inhibitory

> capability. The suppression of gene transcription resulting from the

> addition of PUFA to a high carbohydrate diet: occurs quickly (< 3 h)

> after its addition to a high glucose diet; can be recreated with

> hepatocytes cultured in a serum-free medium containing insulin and

> glucocorticoids; can be demonstrated in diabetic rats fed fructose

>

> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?

db=pubmed & cmd=Retrieve & dopt=AbstractPlus & list_uids=9558724 & query_hl=1 &

itool=pubmed_docsum

>

> Dietary polyunsaturated fatty acids (PUFA) have profound effects on

> hepatic gene transcription leading to significant changes in lipid

> metabolism. PUFA rapidly suppress transcription of genes encoding

> specific lipogenic and glycolytic enzymes and induce genes encoding

> specific peroxisomal and cytochrome P450 (CYP) enzymes.

>

> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?

db=pubmed & cmd=Retrieve & dopt=AbstractPlus & list_uids=10419152 & query_hl=1

& itool=pubmed_DocSum

>

> In another earlier report:

>

> L-type pyruvate kinase (L-PK) is a key glycolytic enzyme regulating

> the flux of metabolites through the pyruvate-phosphoenolpyruvate

cycle

> (1). The regulation of L-PK is complex involving both hormones and

> nutrients. We have found that feeding rats diets containing

> polyunsaturated fatty acids (PUFA) significantly inhibits hepatic

> pyruvate kinase enzyme activity (> 60%) and suppresses mRNAPK

> abundance (> 70%). Studies with primary hepatocytes indicate that

PUFA

> act directly on hepatocytes. Specifically, arachidonic (20:4, omega

6)

> and eicosapentaenoic (20:5, omega 3) acid suppressed both mRNAPK

> llevels and the activity of a transfected PKCAT (-4300/+12) fusion

> gene by > 70%. This is due to an inhibition of the

> insulin/glucose-mediated transactivation of L-PKCAT.

>

> What sense doe we make of all this?