Biomedical subjects

Jonathan R S Arch

Publications and source records attributed to Jonathan R S Arch.

9 recordsLinked to original sources

PubMed2005

Prolonged treatment of genetically obese mice with conjugated linoleic acid improves glucose tolerance and lowers plasma insulin concentration: possible involvement of PPAR activation.

BACKGROUND: Studies in rodents and some studies in humans have shown that conjugated linoleic acid (CLA), especially its trans-10, cis-12 isomer, reduces body fat content. However, some but not all studies in mice and humans (though none in rats) have found that CLA promotes insulin resistance. The molecular mechanisms responsible for these effects are unclear, and there are conflicting reports on the effects of CLA on peroxisomal proliferator-activated receptor-gamma (PPARgamma) activation and expression. We have conducted three experiments with CLA in obese mice over three weeks, and one over eleven weeks. We have also investigated the effects of CLA isomers in PPARgamma and PPARalpha reporter gene assays. RESULTS: Inclusion of CLA or CLA enriched with its trans-10, cis-12 isomer in the diet of female genetically obese (lepob/lepob) mice for up to eleven weeks reduced body weight gain and white fat pad weight. After two weeks, in contrast to beneficial effects obtained with the PPARgamma agonist rosiglitazone, CLA or CLA enriched with its trans-10, cis-12 isomer raised fasting blood glucose and plasma insulin concentrations, and exacerbated glucose tolerance. After 10 weeks, however, CLA had beneficial effects on glucose and insulin concentrations. At this time, CLA had no effect on the plasma TNFalpha concentration, but it markedly reduced the plasma adiponectin concentration. CLA and CLA enriched with either isomer raised the plasma triglyceride concentration during the first three weeks, but not subsequently. CLA enriched with its trans-10, cis-12 isomer, but not with its cis-9, trans-11 isomer, stimulated PPARgamma-mediated reporter gene activity; both isomers stimulated PPARalpha-mediated reporter gene activity. CONCLUSIONS: CLA initially decreased but subsequently increased insulin sensitivity in lepob/lepob mice. Activation of both PPARgamma and PPARalpha may contribute to the improvement in insulin sensitivity. In the short term, however, another mechanism, activated primarily by trans-10, cis-12-CLA, which probably leads to reduced adipocyte number and consequently reduced plasma adiponectin concentration, may decrease insulin sensitivity.

Adiponectin↗

PubMed2005

Central regulation of energy balance: inputs, outputs and leptin resistance.

The regulation of energy balance is complex and, in man, imprecise. Nevertheless, in many individuals intake and expenditure are balanced with <1% error with little or no conscious effect. Essential components of such a regulatory system are signals, leptin and insulin, that reflect the size of lipid stores. Leptin receptors signal via phosphatidylinositol 3-kinase (as do insulin receptors) and via the transcription factor signal transducer and activator of transcription-3 to activate various types of neurone. Obese rodents, and possibly man, are resistant to leptin; in some cases because of genetic or perinatal programming (primary resistance), but commonly in response to high leptin levels (secondary resistance). Secondary leptin resistance may be a result of reduced transport of leptin to the brain or down-regulation of leptin signalling. Signals that reflect lipid stores form the tonic homeostatic regulatory system. They interact with episodic homeostatic signals carried by neurones, hormones and metabolites to regulate meal size and frequency. They also interact with signals related to the palatability of food, biorhythms and learning. Many neurotransmitters and hormones mediate responses to more than one input (e.g. gastric and adipocyte leptin), but are nevertheless most involved with particular inputs (e.g. leptin with adipocyte fat stores). Feeding can be divided into appetitive (preparation for feeding) and consummatory phases, which can both be further subdivided. Different sets of neurotransmitters and hormones are involved at each stage. In the long term it may be possible to customise obesity therapies according to those inputs and outputs that are most disturbed and most amenable to intervention in individual subjects.

Adipose Tissue↗

PubMed2005

Fetal origins of insulin resistance and obesity.

A number of epidemiological studies worldwide have demonstrated a relationship between poor early growth and an increased susceptibility to insulin resistance, visceral obesity, type 2 diabetes and other features of the metabolic syndrome in adulthood. However, the mechanistic basis of this relationship and the relative roles of genes and the environment remain a subject of debate. The 'thrifty phenotype' hypothesis proposes that poor fetal nutrition leads to programming of metabolism and an adult phenotype that is adapted to poor but not plentiful nutrition. The maternal reduced-protein rat model has been used to examine the importance of the maternal environment in determining susceptibility to adult disease. Pregnant and lactating rat dams are fed a diet containing 80 g protein/kg as compared with 200 g protein/kg, which leads to growth restriction in utero. Offspring of low-protein dams have increased susceptibility to diabetes, insulin resistance and hypertension when fed a palatable high-fat diet that promotes obesity. Administration of leptin during pregnancy and lactation to these protein-restricted dams produces offspring that have increased metabolic rate and do not become obese or insulin resistant when fed on a high-fat diet. Increased glucocorticoid exposure, particularly during late gestation, has been linked with insulin resistance in adulthood. High levels of fetal glucocorticoids may result from a decreased activity of placental 11beta-hydroxysteroid dehydrogenase (11beta-HSD) type 2, which normally protects the fetus from high maternal glucocorticoid levels. Leptin administration to protein-restricted dams inhibits the suppression of 11beta-HSD-2 and may be one mechanism by which the metabolic syndrome is prevented.

Animals↗

PubMed2004

Development of glucose intolerance in male transgenic mice overexpressing human glycogen synthase kinase-3beta on a muscle-specific promoter.

Glycogen synthase kinase-3 (GSK-3) protein levels and activity are elevated in skeletal muscle in type 2 diabetes, and inversely correlated with both glycogen synthase activity and insulin-stimulated glucose disposal. To explore this relationship, we have produced transgenic mice that overexpress human GSK-3beta in skeletal muscle. GSK-3beta transgenic mice were heavier, by up to 20% (P < .001), than their age-matched controls due to an increase in fat mass. The male GSK-3beta transgenic mice had significantly raised plasma insulin levels and by 24 weeks of age became glucose-intolerant as determined by a 50% increase in the area under their oral glucose tolerance curve (P < .001). They were also hyperlipidemic with significantly raised serum cholesterol (+90%), nonesterified fatty acids (NEFAs) (+55%), and triglycerides (+170%). At 29 weeks of age, GSK-3beta protein levels were 5-fold higher, and glycogen synthase activation (-27%), glycogen levels (-58%) and insulin receptor substrate-1 (IRS-1) protein levels (-67%) were significantly reduced in skeletal muscle. Hepatic glycogen levels were significantly increased 4-fold. Female GSK-3beta transgenic mice did not develop glucose intolerance despite 7-fold overexpression of GSK-3beta protein and a 20% reduction in glycogen synthase activation in skeletal muscle. However, plasma NEFAs and muscle IRS-1 protein levels were unchanged in females. We conclude that overexpression of human GSK-3beta in skeletal muscle of male mice resulted in impaired glucose tolerance despite raised insulin levels, consistent with the possibility that elevated levels of GSK-3 in type 2 diabetes are partly responsible for insulin resistance.

Animals↗

PubMed2004

Do low-affinity states of beta-adrenoceptors have roles in physiology and medicine?

The pharmacology once ascribed to the 'beta4-adrenoceptor' is now believed to be that of a low-affinity state of the beta1-adrenoceptor. The beta2-adrenoceptor may also have a low-affinity state or site, while the beta3-adrenoceptor--the original low-affinity beta-adrenoceptor--can display more than one pharmacology. In this issue, Mallem et al. show that CGP-12177 relaxes thoracic aorta rings from normal rats by stimulating vascular smooth muscle low-affinity beta1-adrenoceptors, apparently linked in part to Gi protein. By contrast, in rings from hypertensive rats, CGP-12177 acts mainly via endothelial beta3-adrenoceptors. This work raises the possibility that low-affinity states of beta-adrenoceptors have physiological roles, and suggests that they might be drug targets.

Aorta, Thoracic↗

PubMed2002

beta(3)-Adrenoceptor agonists: potential, pitfalls and progress.

beta(3)-Adrenoceptor agonists are very effective thermogenic anti-obesity and insulin-sensitising agents in rodents. Their main sites of action are white and brown adipose tissue, and muscle. beta(3)-Adrenoceptor mRNA levels are lower in human than in rodent adipose tissue, and adult humans have little brown adipose tissue. Nevertheless, beta(3)-adrenoceptors are expressed in human white as well as brown adipose tissue and in skeletal muscle, and they play a role in the regulation of energy balance and glucose homeostasis. It is difficult to identify beta(3)-adrenoceptor agonist drugs because the pharmacology of both beta(3)- and beta(1)-adrenoceptors can vary; near absolute selectivity is needed to avoid beta(1/2)-adrenoceptor-mediated side effects and selective agonists tend to have poor oral bioavailability. All weight loss is lipid and lean may actually increase, so reducing weight loss relative to energy loss. beta(3)-adrenoceptor agonists have a more rapid insulin-sensitising than anti-obesity effect, possibly because stimulation of lipid oxidation rapidly lowers intracellular long-chain fatty acyl CoA and diacylglycerol levels. This may deactivate those protein kinase C isoenzymes that inhibit insulin signalling.

Adrenergic beta-3 Receptor Agonists↗

PubMed2002

Orexins and the treatment of obesity.

Orexin-A and -B are two peptides derived by proteolytic cleavage from a 130-amino acid precursor, prepro-orexin, which were recently isolated from the rat hypothalamus. Orexin-A is fully conserved across mammalian species, whilst rat and human orexin-B differ by two amino acids. These peptides bind to two Gq-coupled receptors, termed orexin-1 and orexin-2. The receptors are 64% homologous and highly conserved across species. Orexin-A is equipotent at orexin-1 and orexin-2 receptors, whilst orexin-B displays moderate (approximately 10 fold) selectivity for orexin-2 receptors. The distribution and pharmacology of the orexin peptides and their receptors indicate that they play a role in various regulatory systems including energy homeostasis and the regulation of feeding, the evidence for which is reviewed here.

Animals↗

PubMed2002

Orexins and feeding: special occasions or everyday occurrence?

Neurons expressing prepro-orexin, the precursor of orexin-A and -B, are found in the lateral hypothalamic area, a region classically implicated in driving feeding. Orexin-A induces feeding transiently when injected centrally, and food intake can be decreased when orexin action is disrupted by immunoneutralization of orexin-A, or by pharmacological blockade of orexin receptors, or by transgenic knockout of orexin. Here, we argue that orexin neurons may act to stimulate feeding in the short term, and that important regulatory signals may be a fall in plasma glucose (stimulatory), countered by satiety signals generated by eating, such as gastric distention (inhibitory).

Animals↗

PubMed2002

Anorectic, thermogenic and anti-obesity activity of a selective orexin-1 receptor antagonist in ob/ob mice.

A single dose of the orexin-1 (OX1) receptor antagonist 1-(2-methylbenzoxazol-6-yl)-3-[1,5] naphthyridin-4-yl urea hydrochloride (SB-334867-A) reduces orexin-A-induced feeding and natural feeding in Sprague Dawley rats. In this study, the anti-obesity effects of SB-334867-A were determined in genetically obese (ob/ob) mice dosed with SB-334867-A (30 mg/kg, i.p.) once daily for 7 days, and then twice daily for a further 7 days. SB-334867-A reduced cumulative food intake and body weight gain over 14 days. Total fat mass gain, determined by Dual Emission X-ray Absorptiometry, was reduced, while gain in fat-free mass was unchanged. Fasting (5 h) blood glucose was also reduced at the end of the study, with a trend to reduced plasma insulin. Interscapular brown adipose tissue (BAT) weight was reduced, the tissue was noticeably darker in colour and quantitative PCR (TaqMan) analysis of this tissue showed a trend to an increase in uncoupling protein-1 mRNA expression, suggesting that SB-334867-A might stimulate thermogenesis. This was confirmed in a separate study in which a single dose of SB-334867-A (30 mg/kg, i.p.) increased metabolic rate over 4 h in ob/ob mice. OX1 receptor mRNA was detected in BAT, and its expression was increased by 58% by treatment with SB-334867-A. This is the first demonstration that OX1 receptor antagonists have potential as both anti-obesity and anti-diabetic agents.

Adipose Tissue, Brown↗