Re: Fat Cells

[Guest guest]

I have not seen any reports, and neither has my doctor, that say HIV medications are altering our DNA, which in my understanding is the only way new fat cells would be prevented from being created. As for defective lipogenesis (fat synthesis) and increased metabolic activity, neither one of those processes has to do with fat cells dying, but with the way fat cells store or do not store fat.

There are several studies from Australia (Drs Mallal and Nolan) that fat cells under the skin "starve off" by not storing triglycerides and then macrophages (the cells that clean debris) come in and eat them up. Mitochondrial toxity (sharp decrease in Mitcondrial DNA) in fat cells has been reported in many studies. It is drastic with Zerit and DDC and less so with AZT. So, fat cells not only "starve" but do not reproduce as effectively with lower DNA levels in their mitochondria.

Evidence of Toxicity in Adipose Tissue of HIV-infected Patients Correlates with NRTI-associated mtDNA Depletion.

Hammond E, Nolan D, I, McKinnon E, White A, Mallal S.Conf Retroviruses Opportunistic Infect. 2003 Feb 10-14;10:abstract no. 759.

Ctr for Clin Immunology and BioMed Statistics, Western Australia

BACKGROUND: The proposed basis for NRTI-associated fat wasting involves cellular mitochondrial DNA (mtDNA) depletion and mitochondrial dysfunction leading to clinical toxicities. We have investigated the relationship between NRTI therapy and mtDNA depletion in adipocytes using cross sectional data from the West Australian HIV cohort. Longitudinal samples were then used to investigate associations between mtDNA depletion and adipose tissue toxicity. METHODS: Cross sectional data: Excisional biopsy fat samples (n = 78) were collected from 60 patients (pts). mtDNA copies/cell was determined after collagenase treatment using real-time PCR. Statistical analysis was performed using linear mixed effects models. Longitudinal data: Adipose biopsies (n = 19) were obtained from suprailiac and buffalo hump sites from 9 HIV-infected pts before and after commencing/switching NRTI therapy, and in one healthy control. mtDNA copies/cell was determined as above. Immunohistochemistry, using fluorescent probes and confocal microscopy to assess mitochondrial (I) and nuclear encoded (IV) subunits of cytochrome c oxidase, was performed on frozen biopsies. RESULTS: Cross sectional Data: Current NRTI therapy was the dominant determinant of mtDNA content with reduced average mtDNA associated with d4T (n = 22, 234 copies/cell, p < 0.0001) and AZT therapy (n = 15, 537 copies/cell, p = 0.002) compared with no NRTI (n = 23, 1,622 copies/cell). Longitudinal Data: All tissue with NRTI-associated mtDNA depletion ( CONCLUSIONS: Increasing adipocyte mtDNA depletion correlates with a gradation of toxicity in adipose tissue. Our findings are consistent with a model in which inhibition of mtDNA synthesis by NRTIs has mild to severe toxic outcomes in adipocytes (depending on choice of NRTI) which ultimately contributes to the severity of fat wasting.

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[Guest guest]

At 07:09 PM 11/19/2004 -0500, you wrote:

>This is not my understanding. I believe the fat cells are actually

>damaged and destroyed. I wouldn't be money on any single explanation,

>though.

I think that's right, . I looked at PubMed and copy a couple of

abstracts. Clearly, some of the fat cells are dying of " apoptosis " or

programmed cell death--a form of cell suicide. But that's not the only

thing going on. As the first abstract notes, " HAART-associated partial

lipodystrophy is probably the result of a remodeling process of fat cells

involving variable combinations of apoptosis, defective lipogenesis, and

increased metabolic activity in different adipose areas of the body. "

Whether this damage is reversible I think is an open question. One study

suggested it may not be reversible (see J Infect Dis. 2001 Nov

1;184(9):1197-201. Epub 2001 Oct 12.). But I don't necessarily buy that.

Lipogenesis occurs in adults, albeit at rates lower than infants and

children (see last abstract). So that aspect may be corrected with time

and/or possibly some hormonal or antioxidant interventions (the balance and

distribution of fat in cells).

As to new production of fat cells (adipocytes), I think that this might

occur in humans--a mouse study suggesting a role for the development of new

adipocytes of PPAR-gamma, which is adversely affected by nucleoside analog

therapy. See:

http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=384783

As an aside, the problematic cytokine, TNF, has been associated with

potential cardiovascular problems:

http://atvb.ahajournals.org/cgi/content/abstract/23/4/695

I don't yet know enough about the subject of preadipocyte development into

adipocytes (whether representing white or brown fat), however, I wouldn't

give up on the body's ability to heal and recover! See also Metabolism.

2003 Aug;52(8):987-92.

M.

**

Lloreta J, Domingo P, Pujol RM, Arroyo JA, Baixeras N, Matias-Guiu X,

Gilaberte M, Sambeat MA, Serrano S. Ultrastructural features of highly

active antiretroviral therapy-associated partial lipodystrophy. Virchows

Arch. 2002 Dec;441(6):599-604. Epub 2002 Oct 24.

Department of Pathology, Hospital del Mar-IMAS-IMIM, Universitat Pompeu

Fabra, Passeig Maritim 25-29, 08003-Barcelona, Spain. Jlloreta@...

Chronic treatment with highly active antiretroviral therapy (HAART) results

in a novel variety of partial lipodystrophy, combining lipoatrophic and

hypertrophic areas. We have previously reported the histopathological

features of this disease and have also shown that adipocyte apoptosis is

involved in its origin. With the aim of further elucidating the mechanisms

underlying this peculiar disorder, we performed an ultrastructural study of

the adipocytes of ten HIV-1-infected patients treated with HAART for 20-42

months. In all ten cases, two main sets of ultrastructural changes were

identified. Some adipocytes showed disruption of cell membranes, fragmented

cytoplasmic rims, irregular cell outlines, and eventually fat droplets

laying free in the connective tissue, with a histiocytic reaction around

them. In addition, many adipocytes showed variable compartmentalization of

fat droplets with decrease in cell size and abundant, mitochondria-rich

cytoplasm. Often, a dual " white and brown " fat appearance was observed with

a large unilocular vacuole surrounded by a rim of multilocular cytoplasm

containing smaller isometric fat droplets and numerous mitochondria. These

findings suggest that HAART-associated partial lipodystrophy is probably

the result of a remodeling process of fat cells involving variable

combinations of apoptosis, defective lipogenesis, and increased metabolic

activity in different adipose areas of the body.

PMID: 12461618 [PubMed - indexed for MEDLINE]

**

Domingo P, Matias-Guiu X, Pujol RM, Francia E, Lagarda E, Sambeat MA,

Vazquez G. Subcutaneous adipocyte apoptosis in HIV-1 protease

inhibitor-associated lipodystrophy. AIDS. 1999 Nov 12;13(16):2261-2267.

Department of Internal Medicine, Hospital de la Santa Creu i Sant Pau,

Universitat Autonoma de Barcelona, Spain. pere.domingo@...

BACKGROUND: Inhibitors of HIV-1 protease produce a rapid decrease in plasma

HIV-1 RNA, with concomitant immune reconstitution. However, severe

metabolic side effects together with a previously unseen form of

lipodystrophy have been associated with long-term use of protease-inhibitor

therapy. The pathogenic mechanisms underlying HIV-1 protease

inhibitor-associated lipodystrophy are still largely unknown. METHODS:

Fourteen HIV-infected patients with HIV-1 protease inhibitor-associated

lipodystrophy had a biopsy of subcutaneous fat performed in the

antero-lateral aspect of the right leg. The samples were submitted for

standard pathologic study together with a careful search for adipocyte

apoptosis. Apoptosis was assessed by the terminal deoxynucleotidyl

transferase dUTP-digoxigenin nick end labelling (TUNEL) method, using the

ApopTag kit (Oncor, Gaithersburg, land, USA). The procedure was

performed between three and five times for each sample. Appropriate

positive and negative controls were used. Controls which were subcutaneous

fat biopsies from patients with untreated melanoma were also examined for

the presence of apoptosis. RESULTS: Fourteen HIV-infected patients with a

mean exposure to HIV-1 protease inhibitors of 12.6 +/- 3.7 months (range:

6-21 months), developed the characteristic features of HIV-1 protease

inhibitor-associated lipodystrophy. All but one patient had an abnormal

waist:hip ratio, and they all exhibited an abnormal serum lipid profile.

Pathologically, subcutaneous fat atrophy was a constant feature, along with

focal lipogranuloma formation and vascular proliferation. One of the eleven

assessable biopsy samples was negative for the presence of apoptosis, six

showed focally positive apoptotic cells, and the remaining four biopsies

demonstrated moderate positivity. Apoptotic changes were also detected in

endothelial cells. Apoptotic changes were more pronounced in patients with

higher increases in CD4 and CD8 counts, and in those with a greater decay

in plasma viral load. CONCLUSIONS: Subcutaneous adipocyte apoptosis occurs

in lipoatrophic areas of patients with HIV-1 protease inhibitor-associated

lipodystrophy.

**

Kamel AF, Norgren S, Strigard K, Thorne A, Fakhrai-Rad H, Galli J, Marcus

C. Age-dependent regulation of lipogenesis in human and rat adipocytes. J

Clin Endocrinol Metab. 2004 Sep;89(9):4601-4606.

Department of Pediatrics, National Childhood Obesity Centre, Children's

Hospital, Huddinge University Hospital, Karolinska Institute, S-141 86

Huddinge, Sweden.

The regulation of adipocyte metabolism is of importance for adipose tissue

growth and therefore also for the development of obesity. This study was

designed to investigate the regulation of basal and insulin-induced

lipogenesis, glucose transport, and glucose transporter protein expression

in human and rat adipocytes from different age groups. The study included

21 infants, 21 children, nine adults, and 80 male weaned and 20 male adult

Fischer rats. The lipogenesis experiments were performed under conditions

at which glucose transport is rate limiting. Basal lipogenesis was

approximately three times higher in infants and children than in adults,

whereas insulin-induced lipogenesis was two times higher in infants than in

children and adults. In rats, basal lipogenesis, insulin-induced

lipogenesis, and insulin sensitivity were two times higher in weaned than

in adult animals. Moreover, basal and insulin-induced glucose transport

were two times higher in weaned than in adult rats. No differences were

detected in GLUT1 or GLUT4 content between any of the age groups in human

or in rat adipocytes. In conclusion, basal and insulin-stimulated

lipogenesis are increased in adipocytes early in life. This may promote

adipose tissue growth in early age. The data indicate that age-dependent

variation in basal and insulin-stimulated lipogenesis is differently regulated.

[Guest guest]

"Clearly, some of the fat cells are dying of 'apoptosis' or programmed cell death--a form of cell suicide. But that's not the only thing going on. As the first abstract notes, "HAART-associated partial lipodystrophy is probably the result of a remodeling process of fat cells involving variable combinations of apoptosis, defective lipogenesis, and increased metabolic activity in different adipose areas of the body."

All cells in the body eventually die, which is why we often hear the statement that every cell in our body is replaced every seven years (though not at the same time, thank heaven!). However, that does not mean that new fat cells are not being created. I have not seen any reports, and neither has my doctor, that say HIV medications are altering our DNA, which in my understanding is the only way new fat cells would be prevented from being created. As for defective lipogenesis (fat synthesis) and increased metabolic activity, neither one of those processes has to do with fat cells dying, but with the way fat cells store or do not store fat.

[Guest guest]

I think that we have to wait over time to see if lost fat can continue to be restored after switching nukes. From TARHEEL & MITOX followup we will be able to see if restoration continues & to what degree. I also agree with Simon that the Carr rosi study needs to be redone. Jules

I think is right. The talks from Paddy Mallon and Nolan at the lipodystrophy workshop included several new pieces of research that were very interesting.

One was identifying that PPAR-gamma is reduced by 50% by AZT and d4T after 2 weeks in HIV negative volunteers using either AZT/3TC or d4T/3TC. The effect continued for 6 weeks after drugs were stopped.

PPAR-gamma is similarly affected by PI's and this may explain why there is a more then added risk of lipoatrophy when both nukes and PIs are used together. The discussion included a suggestion that this could explain why the trials of rosiglitazone for lipoatrophy saw no benefit - because continued use of d4T or AZT cancelled out the action of rosoglitazone in increasing PPAR-gamma.

PPAR-gamma is a gene that is involved with fat cell differentiation - basically how fat cells are produced and mature.

Other genes involved in mitochondrial (mT) function and fatty acid oxidation were also affected this early, sometimes by up to 80%.

The d4T effect is about twice as strong as the AZT effect and the discussions suggested that while both d4T and AZT affect adipocyte differentiation, only d4T is directly toxic to pre-adipocytes. I'd want to see more details on this though.

The Nolan studies showed that other nucleosides - especially abacavir and tenofovir - did not affect mT DNA, mT protein or PPAR-gamma - ie although there were small numbers these levels remained similar to HIV-positive treatment naive patients.

Simon

I have to disagree.  One theory that makes lots of sense to me is that

fat cells are being told to commit suicide via an enzyme signaling

system called "PPAR."  If this happens, the cells are gone.  Their DNA

is  degraded and can no longer be there to direct the deceased fat cell

to reproduce.  That's a pretty definite change in DNA.

HAART drugs absolutely do interfere with the synthesis of human

mitochondrial dna, and I would bet you that some abnormalities will be

found in nuclear dna, as well.

JB

On Nov 20, 2004, at 2:11 PM, PozHealth wrote:

>   However, that does not mean that new fat cells are not being

> created.  I have not seen any reports, and neither has my doctor, that

> say HIV medications are altering our DNA, which in my understanding is

> the only way new fat cells would be prevented from being created.  As

> for defective lipogenesis (fat synthesis) and increased metabolic

> activity, neither one of those processes has to do with fat cells

> dying, but with the way fat cells store or do not store fat.

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