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.

A quantitative study of human fat transplants in obese nude mice and their lean littermates.

Human fat cells from lean donors enlarge on transplantation into obese nude mice (genotype ob/ob nu/nu). On transplantation into lean nude mice human fat cells do not change significantly in size, even though they are much larger than mouse fat cells.

Neuroinsular complex type I: morphology and frequency in lean and genetically obese mice.

No quantitative data are available regarding the rate of occurrence of nerve cells in association with endocrine pancreas (i.e.. neuroinsular complexes type I [NICs]), or the difference in the distribution of NICs in normal and diabetic pancreas. In this report, pancreata from 20-day, 7-week, and 9-month-old lean (Umeå +/?) and obese (Umeå ob/ob) mice, as well as 10-month-old C57BL/6JBom and Umeå ob/ob mice, were analyzed with regard to the association of acetylcholinesterase (AChE)-positive and protein gene product 9.5-like (PGP-LI) immunoreactive perikarya with islets, and not in association with islets. NIC profiles were regularly observed, but were more frequent in the 20-day-old mice than in the 9-month-old +/? and ob/ob mice. The NIC profiles were often located close to a duct or blood vessel, significantly more frequently than islet profiles in general. The data did not reveal any gross abnormality in ob/ob mice as regards the frequency of NICs or the number of AChE-positive and PGP-LI perikarya. However, the 9-month-old ob/ob mice demonstrated smaller clusters of perikarya in their NIC profiles as compared to the other mice, probably reflecting the fact that the perikarya were more widely spread out in the hyperplastic islets of adult ob/ob mice. The results show that NICs are common and represent a substantial proportion of the islets in mouse pancreas, supporting the idea that they play a role in islet physiology.

Muscle growth and satellite cell proliferative activity in obese (OB/OB) mice.

Muscle growth of male obese (ob/ob) and lean mice at 2, 3, 5 and 8 wk were analyzed on the basis of weights of gastrocnemius, plantaris and soleus muscles from each hind leg. The carcasses (prepared by removing skin, viscera, head, feet and tail) were analyzed for fat content so that the effect of phenotype on the relationship between muscle weight and fat-free carcass weight could be assessed. For each age group the obese mice had less muscle relative to fat-free carcass weight than lean mice, with the difference being significant at 3 wk (P less than .05) and 8 wk (P less than .025). The proliferative activity of muscle satellite cells in 2- and 3-wk-old obese and lean mice was measured on isolated muscle fibers by autoradiography. Muscle fiber diameter and number of nuclei/unit length were unaffected by phenotype, but the proportion of muscle nuclei showing proliferative activity was lower (P less than .01) in obese than in lean mice at 2 wk (1.05 vs 1.93%, respectively) and 3 wk of age (.23 vs .59%, respectively). These results are consistent with the suggestion that muscle growth is limited by satellite-cell proliferative activity, although direct evidence for a cause and effect relationship is not provided.

TNF-alpha is required for the attraction of mesenchymal precursors to white adipose tissue in Ob/ob mice.

Most adult tissues harbour a stem cell subpopulation (Mesenchymal Precursors or MPs) that represent a small proportion of the total cell number and have the potential to differentiate into several cell types within the mesenchymal lineage. In adipose tissue, adipocytes account for two-thirds of the total cell number. The remaining cells include blood and endothelial cells, along with adipocyte precursors (adipose MPs). Obesity is defined as an excess of body fat that frequently results in a significant impairment of health. The ob/ob mice bear a mutation in the ob gene that causes a deficiency in the hormone leptin and hence obesity. Here, we present evidence that ob/ob mice have a dramatic decrease in the resident MP pool of several tissues, including squeletal muscle, heart, lung and adipose tissue. Moreover, we show that that there is a migration of MP cells from distant organs, as well as homing of these cells to the adipose tissue mass of the ob/ob mice. We call this process adipotaxis. Once in the adipose tissue, migrant MPs undergoe adipose differentiation, giving rise to new differentiated adipocytes within the adipose mass. Finally, we provide evidence that adipotaxis is largely explained by the production of high levels of Tumor Necrosis Factor-alpha (TNF-alpha) within the ob/ob adipose tissue. The therapeutic implications for human obesity as well as for regenerative medicine are further discussed in this paper.

Genetic obesity and the muscle satellite cell.

The nuclear content of skeletal muscles from lean and obese (ob/ob) male mice was investigated. Four lean and four ob/ob mice were examined at 2, 3, 5, 8, and 16 weeks of age. Differences in body weight between the two phenotypes were significant after 5 weeks of age. For all ages in the soleus and after 3 weeks of age in the gastrocnemius, muscle wet weight and length were less in ob/ob mice than in lean mice. Age did not influence the incidence of myonuclei in fiber cross sections for either muscle. Compared to lean mice the incidence of myonuclei per fiber cross section was significantly lower for ob/ob mice in the soleus muscle but not in the gastrocnemius muscle. The incidence of satellite cells in fiber cross sections and the percentage of nuclei within the basal lamina that were satellite cell nuclei decreased as age increased. Muscle fibers of ob/ob mice contained fewer myonuclei either because of shorter muscle length (gastrocnemius), or because of the combined effect of shorter muscle length and fewer myonuclei per unit length (soleus). The lower apparent number of myonuclei in the muscles of ob/ob mice was associated with a lower apparent number of satellite cells.

[Ultrastructural changes in the organization of plasma membranes in adipocytes of obese mice (ob/ob)]. / Modification ultrastructurale de l'organisation des membranes plasmiques des adipocytes chez les souris obèses (ob/ob)

Freeze-fracture replicas were obtained from adipocytes in control and obese (ob/ob) Mice. Quantitative evaluation of the replicas shows that plasma membranes of adipocytes in ob/ob Mice have 50% less intramembrane particles than plasma membranes in control Mice. Since intra-membrane particles represent, at least in part, the proteins of the membrane, this suggests a decreased protein concentration, as well as a perturbed protein-lipid ratio in adipocyte membranes of obese Mice.

[Existence of cytoplasmic inclusions in acinic cells of the exocrine pancreas of the hyperglycemic obese mouse]. / Sur l'existence d'inclusions cytoplasmiques particulières dans les cellules acineuses du pancréas exocrine de la souris obèse hyperglycémique

Peculiar cytoplasmic inclusions with crystalline pattern are described in the obese hyperglycaemic mouse pancreas acinar cells. They are generally associated with filamentous structures. However, crystalline and filamentous inclusions have also been observed in isolated forms. These inclusions are not digested by pronase. Since they have also been encountered in normal mice, it seems that the hyperglycaemic syndrome does not play a role in inducing their formation.

[Clinico-pathological studies on small obese mice occurring in C57BL/6J-ob/ob mice].

Eight small obese mice, 10 to 79 weeks of age, which occurred in C57BL/6J obese mice, were examined clinico-pathologically. These mice were characterized by small-sized obesity, and showed hyperglycemia without hyperinsulinemia and glucosuria without ketonurina throughout their life span. Morphologically, neither hypertrophy nor hyperplasia were found in the islets of Langerhans. There were an increase of A cells and a decrease of B cells in their islets. In the kidney, thickening of mesangial matrix in glomeruli and deposition of glycogen in the nucleus of epithelial cells of the distal tubules were seen. These findings suggest that the small obese mice are an obese-diabetic animal of different type from the usual obese mice (C57BL/6J-ob/ob). The mechanism for development of this condition was unknown.

Studies on the body composition, fat distribution and fat cell size and number of 'Ad', a new obese mutant mouse.

1. Studies have been performed on the body composition, the fat distribution, the fat cell size, and the 'observable' fat cell number of a new obese mutant, the Adipose (Ad) mouse. The serum glucose and insulin concentrations have also been investigated. All studies were undertaken with animals aged 6 months. 2. The obese animals weighed over 50% more than the lean, but there was no difference in the body or tail lengths. 3. The obese animals had an increase in the weight of the liver, but the increase was only proportional to the increase in the total body-weight. 4. The carcasses of the obese mice contained more water as well as more fat than those of the lean. In the males the fat content was 3.9 times greater, while in the females it was increased by 5.5 times. 5. The nitrogen content of the defatted dry carcass was the same in both lean and obese animals but the total body protein was higher in the obese. 6. Fat was dissected from four major depots, gonadal, abdominal, hind subcutaneous and interscapular subcutaneous (including brown adipose tissue), and each was substantially larger in the obese animals. This indicated that the additional fat of the Ad mouse was not localized to any particular site. 7. In Ad males there was no over-all increase in the observed number of adipocytes, all the extra fat being accommodated by an increase in fat cell size (3.8 times). However, in Ad females there was a 3.3 fold increase in the number of observable fat cells as well as a 2.2-fold increase in fat cell size. 8. Non-fasted obese animals were not hyperglycaemic, but there was a 5.3-fold increase in the concentration of serum insulin. Hyperinsulinemia in the presence of normoglycaemia suggested that the obese animals were insulin resistant.