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PubMed2004

Failure of fat cell proliferation, mitochondrial function and fat oxidation results in ectopic fat storage, insulin resistance and type II diabetes mellitus.

BACKGROUND: It is widely accepted that increasing adiposity is associated with insulin resistance and increased risk of type II diabetes. The predominant paradigm used to explain this link is the portal/visceral hypothesis. This hypothesis proposes that increased adiposity, particularly in the visceral depots, leads to increased free-fatty acid flux and inhibition of insulin-action via Randle's effect in insulin-sensitive tissues. OBJECTIVES: In this review, limitations of this paradigm will be discussed and two other paradigms that may explain established links between adiposity and insulin resistance/diabetes will be presented. (A) Ectopic fat storage syndrome. Three lines of evidence support this concept. Firstly, failure to develop adequate adipose tissue mass (also known as 'lipodystrophy') results in severe insulin resistance and diabetes. This is thought to be the result of ectopic storage of lipid into liver, skeletal muscle and the pancreatic insulin-secreting beta cell. Secondly, most obese patients also shunt lipid into the skeletal muscle, the liver and probably the beta cell. The importance of this finding is exemplified by several studies demonstrating that the degree of lipid infiltration into skeletal muscle and liver highly correlates with insulin resistance. Thirdly, increased fat cell size is highly associated with insulin resistance and the development of diabetes. Increased fat cell size may represent the failure of the adipose tissue mass to expand and therefore to accommodate an increased energy influx. Taken together, these observations support the 'acquired lipodystrophy' hypothesis as a link between adiposity and insulin resistance. Ectopic fat deposition is therefore the result of additive or synergistic effects including increased dietary intake, decreased fat oxidation and impaired adipogenesis. (B) Endocrine paradigm. This concept was developed in parallel with the 'ectopic fat storage syndrome' hypothesis. Adipose tissue secretes a variety of endocrine hormones such as leptin, interleukin-6, angiotensin II, adiponectin and resistin. From this viewpoint, adipose tissue plays a critical role as an endocrine gland, secreting numerous factors with potent effects on the metabolism of distant tissues. CONCLUSIONS: The novel paradigms of ectopic fat and fat cell as an endocrine organ probably will constitute a new framework for the study of the links between our obesigenic environment and the risk of developing diabetes.

Adipocytes↗
PubMed1972

Oxidative phosphorylation. The effect of anions on the inhibition by triethyltin of various mitochondrial functions, and the relationship between this inhibition and binding of triethyltin.

1. The binding of triethyltin to rat liver mitochondria is unaffected by the nature of the predominant anion in the incubation medium. 2. With chloride, bromide or iodide as the predominant anion, ATP synthesis linked to the oxidation of pyruvate or succinate and ATP hydrolysis stimulated by 2,4-dinitrophenol are much more sensitive to triethyltin than they are when nitrate or isethionate is the predominant anion. 3. When nitrate or isethionate is the predominant anion, oxygen uptake stimulated by 2,4-dinitrophenol is not inhibited by triethyltin. 4. In the presence of nitrate or isethionate anions, inhibition of ATP synthesis is directly related to the binding of triethyltin to mitochondria. 5. The relationship of the above effects to the anion-hydroxide ion exchange mediated by triethyltin and the relevance of this to published arrangements for coupling of electron transport to ATP synthesis are discussed.

Adenosine Triphosphate↗
PubMed2004

Oxidative stress and mitochondrial function with aging--the effects of calorie restriction.

Accumulated oxidative stress resulting from a gradual shift in the redox status of tissues is now considered to be a key mechanism underlying the aging process. Calorie-restricted (CR) feeding, an experimental protocol to extend survival and delay aging in rodents, is recognized to slow the rate of accrual of age-related oxidative stress. This conclusion is based on the increase in tissues with age of the oxidation products of proteins, lipids and DNA. The functional consequence, however, of the accumulation of these non-specific oxidative markers is more difficult to determine. A shift in the redox status of tissues with age and calorie restriction feeding may have a greater impact on cell function through activation of redox sensitive transcription factors than through the accumulation of these non-specific oxidative markers. Activation of such transcription factors will stimulate signalling pathways that will lead to a change in the gene expression profile and cell functioning. Little research has been conducted in this area. It has been proposed that CR feeding slows the rate of accrual of oxidative damage because mitochondria in these animals have a lower rate of superoxide generation when compared with mitochondria from control animals. This proposal is based on in vitro observations using isolated mitochondria and clearly requires further confirmation in isolated cells or using an in vivo approach. The application of metabolic control analysis to identify in isolated mitochondria the mechanism underlying this response has suggested one possible explanation for the lower superoxide production rates observed.

Aging↗
PubMed2001

Mitochondrial function and oxygen supply in normal and in chronically ischemic muscle: a combined 31P magnetic resonance spectroscopy and near infrared spectroscopy study in vivo.

PURPOSE: We used (31)P magnetic resonance spectroscopy (MRS) and near-infrared spectroscopy (NIRS) as a means of quantifying abnormalities in calf muscle oxygenation and adenosine triphosphate (ATP) turnover in peripheral vascular disease (PVD). METHODS: Eleven male patients with PVD (mean age, 65 years; range, 55-76 years) and nine male control subjects of similar age were observed in a case-control study in vascular outpatients. Inclusion criteria were more than 6 months' calf claudication (median, 1.5 years; range, 0.6-18 years); proven femoropopliteal or iliofemoral occlusive or stenotic disease; maximum treadmill walking distance (2 km/h, 10 degrees gradient) of 50 to 230 m (mean, 112 m); ankle-brachial pressure index of 0.8 or less during exercise (mean, 0.47; range, 0.29-0.60). Exclusion criteria included diabetes mellitus, anemia, and magnet contraindications. Simultaneous (31)P MRS and NIRS of lateral gastrocnemius was conducted during 2 to 4 minutes of voluntary 0.5 Hz isometric plantarflexion at 50% and 75% maximum voluntary contraction force (MVC), followed by 5 minutes recovery. Each subject was studied three times, and the results were combined. RESULTS: Compared with control subjects, patients with PVD showed (1) normal muscle cross-sectional area, MVC, ATP turnover, and contractile efficiency (ATP turnover per force/area); (2) larger phosphocreatine (PCr) changes during exercise (ie, increased shortfall of oxidative ATP synthesis) and slower PCr recovery (47% +/- 7% [mean +/- SEM] decrease in functional capacity for oxidative ATP synthesis, P = .001); (3) faster deoxygenation during exercise and slower postexercise reoxygenation (59% +/- 7% decrease in rate constant, P = .0009), despite reduced oxidative ATP synthesis; (4) correlation between PCr and NIRS recovery rate constants (P < .02); and (5) correlations between smaller walking distance, slower PCr recovery, and reduced MVC (P < .001). The precision of the key measurements (rate constants and contractile efficiency) was 12% to 18% interstudy and 30% to 40% intersubject. CONCLUSION: The primary lesion in oxygen supply dominates muscle metabolism. Reduced force-generation in patients who are affected more may protect muscle from metabolic stress.

Adenosine Triphosphate↗
PubMed1984

The action of beta-adrenoceptor antagonists on rat heart mitochondrial function in vitro: a comparison of propranolol, timolol, and atenolol.

The effect of beta-adrenoceptor antagonists, propranolol, timolol and atenolol on functions of rat heart mitochondria in vitro was investigated. Concentrations of all three drugs less than 2 mmol X litre-1 did not affect rates of respiration of uncoupled intact mitochondria supported by substrates of alpha-oxoglutarate, pyruvate-malate or succinate. Inhibition was observed if mitochondria were broken to allow access of substrates and drugs into the mitochondria. Studies of the effect of drug concentration on NADH-supported oxygen uptake and NADH oxidase activity of submitochondrial particles produced from rat heart mitochondria showed a marked inhibition by propranolol: the effect of timolol and atenolol were much less marked and inhibition was only observed at relatively high concentrations of these drugs. Transfer of electrons through Complex I measured by the rate of reduction of ferricyanide by submitochondrial particles inhibited by rotenone and the lack of specific inhibition by propranolol of succinate supported respiration indicated that one site of drug action was between NADH dehydrogenase and its associated flavoprotein, possibly close to the site of rotenone inhibition.

Animals↗
PubMed1988

A functional mitochondrial ATP synthase proteolipid gene produced by recombination of parental genes in a petunia somatic hybrid.

A novel ATP synthase subunit 9 gene (atp9) was identified in the mitochondrial genome of a Petunia somatic hybrid line (13-133) which was produced from a fusion between Petunia lines 3688 and 3704. The novel gene was generated by intergenomic recombination between atp9 genes from the two parental plant lines. The entire atp9 coding region is represented on the recombinant gene. Comparison of gene sequences indicate that the 5' transcribed region is contributed by an atp9 gene from 3704 and the 3' transcribed region is contributed by an atp9 gene from 3688. The recombinant atp9 gene is transcriptionally active. The location of the 5' and 3' transcript termini are conserved with respect to the parental genes, resulting in the production of hybrid transcripts.

Amino Acid Sequence↗