Influence of Dietary Conjugated Linoleic Acid and Fat Source on Body Fat and Apoptosis in Mice*

Objective: To determine whether altered dietary essential fatty acid (linoleic and arachidonic acid) concentrations alter sensitivity to conjugated linoleic acid (CLA)‐induced body fat loss or DNA fragmentation. Research Methods and Procedures: Mice were fed diets containing soy oil (control), coconut oil [essential fatty acid deficient (EFAD)], or fish oil (FO) for 42 days, and then diets were supplemented with a mixture of CLA isomers (0.5% of the diet) for 14 days. Body fat index, fat pad and liver weights, DNA fragmentation in adipose tissue, and fatty acid profiles of adipose tissue were determined. Results: The EFAD diet decreased (p < 0.05) linoleic and arachidonic acid in mouse adipose tissue but did not affect body fat. Dietary CLA caused a reduction (p < 0.05) in body fat. Mice fed the EFAD diet and then supplemented with CLA exhibited a greater reduction (p < 0.001) in body fat (20.21% vs. 6.94% in EFAD and EFAD + CLA‐fed mice, respectively) compared with mice fed soy oil. Dietary FO decreased linoleic acid and increased arachidonic acid in mouse adipose tissue. Mice fed FO or CLA were leaner (p < 0.05) than control mice. FO + CLA‐fed mice did not differ in body fat compared with FO‐fed mice. Adipose tissue apoptosis was increased (p < 0.001) in CLA‐supplemented mice and was not affected by fat source. Discussion: Reductions in linoleic acid concentration made mice more sensitive to CLA‐induced body fat loss only when arachidonic acid concentrations were also reduced. Dietary essential fatty acids did not affect CLA‐induced DNA fragmentation.     

t10c12-CLA maintains higher bone mineral density during aging by modulating osteoclastogenesis and bone marrow adiposity

Conjugated linoleic acid (CLA) has been shown to positively influence calcium and bone metabolism. Earlier, we showed that CLA (equal mixture of c9t11-CLA and t10c12-CLA) could protect age-associated bone loss by modulating inflammatory markers and osteoclastogenesis. Since, c9t11-CLA and t10c12-CLA isomers differentially regulate functional parameters and gene expression in different cell types, we examined the efficacy of individual CLA isomers against age-associated bone loss using 12 months old C57BL/6 female mice fed for 6 months with 10% corn oil (CO), 9.5% CO + 0.5% c9t11-CLA, 9.5% CO + 0.5% t10c12-CLA or 9.5% CO + 0.25% c9t11-CLA + 0.25% t10c12-CLA. Mice fed a t10c12-CLA diet maintained a significantly higher bone mineral density (BMD) in femoral, tibial and lumbar regions than those fed CO and c9t11-CLA diets as measured by dual-energy-X-ray absorptiometry (DXA). The increased BMD was accompanied by a decreased production of osteoclastogenic factors, that is, RANKL, TRAP5b, TNF-alpha and IL-6 in serum. Moreover, a significant reduction of high fat diet-induced bone marrow adiposity was observed in t10c12-CLA fed mice as compared to that of CO and c9t11-CLA fed mice, as measured by Oil-Red-O staining of bone marrow sections. In addition, a significant reduction of osteoclast differentiation and bone resorbing pit formation was observed in t10c12-CLA treated RAW 264.7 cell culture stimulated with RANKL as compared to that of c9t11-CLA and linoleic acid treated cultures. In conclusion, these findings suggest that t10c12-CLA is the most potent CLA isomer and it exerts its anti-osteoporotic effect by modulating osteoclastogenesis and bone marrow adiposity.     

High fat diet-induced animal model of age-associated obesity and osteoporosis

Osteoporosis and obesity remain a major public health concern through its associated fragility and fractures. Several animal models for the study of osteoporotic bone loss, such as ovariectomy (OVX) and denervation, require unique surgical skills and expensive set up. The challenging aspect of these age-associated diseases is that no single animal model exactly mimics the progression of these human-specific chronic conditions. Accordingly, to develop a simple and novel model of post menopausal bone loss with obesity, we fed either a high fat diet containing 10% corn oil (CO) or standard rodent lab chow (LC) to 12-month-old female C57Bl/6J mice for 6 months. As a result, CO fed mice exhibited increased body weight, total body fat mass, abdominal fat mass and reduced bone mineral density (BMD) in different skeletal sites measured by dual energy X-ray absorptiometry. We also observed that decreased BMD with age in CO fed obese mice was accompanied by increased bone marrow adiposity, up-regulation of peroxisome proliferator-activated receptor γ, cathepsin k and increased proinflammatory cytokines (interleukin 6 and tumor necrosis factor α) in bone marrow and splenocytes, when compared to that of LC fed mice. Therefore, this appears to be a simple, novel and convenient age-associated model of post menopausal bone loss, in conjunction with obesity, which can be used in pre-clinical drug discovery to screen new therapeutic drugs or dietary interventions for the treatment of obesity and osteoporosis in the human population.     

Type I diabetic bone phenotype is location but not gender dependent

Bone is highly dynamic and responsive. Bone location, bone type and gender can influence bone responses (positive, negative or none) and magnitude. Type I diabetes induces bone loss and increased marrow adiposity in the tibia. We tested if this response exhibits gender and location dependency by examining femur, vertebrae and calvaria of male and female, control and diabetic BALB/c mice. Non-diabetic male mice exhibited larger body, muscle, and fat mass, and increased femur BMD compared to female mice, while vertebrae and calvarial bone parameters did not exhibit gender differences. Streptozotocin-induced diabetes caused a reduction in BMD at all sites examined irrespective of gender. Increased marrow adiposity was evident in diabetic femurs and calvaria (endochondrial and intramembranous formed bones, respectively), but not in vertebrae. Leptin-deficient mice also exhibit location dependent bone responses and we found that serum leptin levels were significantly lower in diabetic compared to control mice. However, in contrast to leptin-deficient mice, the vertebrae of T1-diabetic mice exhibit bone loss, not gain. Taken together, our findings indicate that TI-diabetic bone loss in mice is not gender, bone location or bone type dependent, while increased marrow adiposity is location dependent.     

Evidence that the anti-obesity effect of conjugated linoleic acid is independent of effects on stearoyl-CoA desaturase1 expression and enzyme activity

The trans-10,cis-12 isomer of conjugated linoleic acid (CLA) reduces body fat gain in animals and inhibits stearoyl-CoA desaturase (SCD) activity in 3T3-L1 adipocytes. To test whether CLA's body fat reduction is mediated by SCD1, wild-type and SCD1-null mice were fed diet supplemented with 0.2% trans-10,cis-12 (t10c12) CLA for 4 weeks. The t10c12 CLA-supplemented diet significantly reduced body fat mass in both wild type and SCD1-null mice. Similarly, t10c12 CLA diet decreased blood triglyceride and free fatty acid levels regardless of SCD1 genotypes. Mice fed t10c12 CLA exhibited increased mRNA expression of fatty acid synthase and uncoupling protein 2 in both genotypes. Taken together, the effects of t10c12 CLA on reduction of body fat gain, blood parameters, and mRNA expression in both SCD1-null mice and wild-type mice were similar, indicating that the anti-obesity effect of t10c12 CLA may be independent of the effects of this CLA isomer on SCD1 gene expression and enzyme activity.     

Differential effects of conjugated linoleic acid isomers in insulin-resistant female C57Bl/6J mice

Obesity is associated with a high risk of developing diabetes and cardiovascular disease. Therefore, management of body weight to prevent obesity remains as an important priority. The present investigation addresses the effects of conjugated linoleic acid (CLA) isomers on body weight and composition of body fat in female C57Bl/6J mice. To investigate the differential effects of individual CLA isomers and their mixture on changes in lean mass, fat mass, glucose and insulin, 6-month-old female C57BL/6J mice were fed with 10% corn oil (CO) as a dietary fat source and either supplemented with purified cis 9,trans 11 (c9t11) CLA (0.5%) or trans 10,cis 12 (t10c12) CLA (0.5%) and/or their mixture (50:50) for 6 months. As a result of 6 months' dietary intervention, both the t10c12-CLA and CLA mix showed increased lean mass and reduced fat mass compared to the CO and c9t11-CLA groups. Insulin resistance was, however, increased in t10c12-CLA and CLA mix-fed groups based on the results of homeostasis model assessment (HOMA), the revised quantitative insulin-sensitivity check index (R-QUICKI) and also with intravenous glucose tolerance test (IVGTT). In conclusion, long-term feeding of the major CLA isomers in 12-month-old C57Bl/6J mice revealed a contrasting effect on fat mass, glucose and insulin metabolism. The t10c12 isomer is found to reduce the fat mass and increase the lean mass but significantly contributed to increase insulin resistance and liver steatosis, whereas c9t11 isomer prevented the insulin resistance.     

Dietary coconut oil increases conjugated linoleic acid-induced body fat loss in mice independent of essential fatty acid deficiency

Conjugated linoleic acid (CLA) induces a body fat loss that is enhanced in mice fed coconut oil (CO), which lacks essential fatty acids (EFA). Our objective was to determine if CO enhancement of CLA-induced body fat loss is due to the lack of EFA. The CLA-EFA interaction was tested by feeding CO and fat free (FF) diets for varying times with and without replenishment of individual EFA. Mice fed CO during only the 2-week CLA-feeding period did not differ from control mice in their adipose EFA content but still tended (P=0.06) to be leaner than mice fed soy oil (SO). Mice raised on CO or FF diets and fed CLA were leaner than the SO+CLA-fed mice (P<0.01). Mice raised on CO and then replenished with linoleic, linolenic, or arachidonic acid were leaner when fed CLA than mice raised on SO (P<0.001). Body fat of CO+CLA-fed mice was not affected by EFA addition. In summary, CO-fed mice not lacking in tissue EFA responded more to CLA than SO-fed mice. Also, EFA addition to CO diets did not alter the enhanced response to CLA. Therefore, the increased response to CLA in mice raised on CO or FF diets appears to be independent of a dietary EFA deficiency.     

Flaxseed oil and inflammation-associated bone abnormalities in interleukin-10 knockout mice

Interleukin-10-/- (IL-10) knockout (KO) mice develop an intestinal inflammation that closely mimics human inflammatory bowel disease (IBD) which is accompanied by inflammation-associated bone abnormalities and elevated serum proinflammatory cytokines. The objective of this study was to use the IL-10 KO mouse model to determine whether flaxseed oil (FO) diet, rich in alpha-linolenic acid (ALA), attenuates intestinal inflammation and inflammation-associated bone abnormalities, compared to a corn oil (CO) control diet. Male wild-type (WT) or IL-10 KO mice were fed a 10% CO or 10% FO diet from weaning (postnatal day 28) for 9 weeks. At necropsy, serum, intestine, femurs and lumbar vertebrae were collected and analyzed. IL-10 KO mice fed CO had lower femur bone mineral content (BMC; P<.001), bone mineral density (BMD; P<.001), peak load (P=.033) and lumbar vertebrae BMD (P=.02) compared to WT mice fed either diet. Flaxseed oil had a modest, favorable effect on IL-10 KO mice as femur BMC, BMD and peak load were similar to WT mice fed CO or FO. In addition, lumbar vertebra BMD was similar among IL-10 KO mice fed FO and WT mice fed CO or FO. The fact that FO attenuated serum tumor necrosis factor-alpha (TNF-alpha) among IL-10 KO mice suggests that the positive effects of FO on femur BMC, BMD, peak load and vertebral BMD in IL-10 KO mice may have been partly mediated by changes in serum TNF-alpha. In conclusion, these findings suggest that a dietary level of ALA attainable from a 10% flaxseed oil diet results in modest improvements in some bone outcomes but does not attenuate intestinal inflammation that is characteristic of IL-10 KO mice.     

Effects of dietary fat energy restriction and fish oil feeding on hepatic metabolic abnormalities and insulin resistance in KK mice with high-fat diet-induced obesity

We investigated the effects of dietary fat energy restriction and fish oil intake on glucose and lipid metabolism in female KK mice with high-fat (HF) diet-induced obesity. Mice were fed a lard/safflower oil (LSO50) diet consisting of 50 energy% (en%) lard/safflower oil as the fat source for 12 weeks. Then, the mice were fed various fat energy restriction (25 en% fat) diets — LSO, FO2.5, FO12.5 or FO25 — containing 0, 2.5, 12.5, or 25 en% fish oil, respectively, for 9 weeks. Conversion from a HF diet to each fat energy restriction diet significantly decreased final body weights and visceral and subcutaneous fat mass in all fat energy restriction groups, regardless of fish oil contents. Hepatic triglyceride and cholesterol levels markedly decreased in the FO12.5 and FO25 groups, but not in the LSO group. Although plasma insulin levels did not differ among groups, the blood glucose areas under the curve in the oral glucose tolerance test were significantly lower in the FO12.5 and FO25 groups. Real-time polymerase chain reaction analysis showed fatty acid synthase mRNA levels significantly decreased in the FO25 group, and stearoyl-CoA desaturase 1 mRNA levels markedly decreased in the FO12.5 and FO25 groups. These results demonstrate that body weight gains were suppressed by dietary fat energy restriction even in KK mice with HF diet-induced obesity. We also suggested that the combination of fat energy restriction and fish oil feeding decreased fat droplets and ameliorated hepatic hypertrophy and insulin resistance with suppression of de novo lipogenesis in these mice.     

Diet‐induced Obese Mice Are Leptin Insufficient After Weight Reduction

Behavioral therapies aimed at reducing excess body fat result in limited fat loss after dieting. To understand the causes for maintenance of adiposity, high‐fat (HF) diet–induced obese (DIO) mice were switched to a low‐fat chow diet, and the effects of chow on histological and molecular alterations of adipose tissue and metabolic parameters were examined. DIO mice reduced and stabilized their body weights after being switched to chow (HF‐chow), but retained a greater amount of adiposity than chow‐fed mice. Reduction in adipocyte volume, not number, caused a decrease in fat mass. HF‐chow mice showed normalized circulating insulin and leptin levels, improved glucose tolerance, and reduced inflammatory status in white adipose tissue (WAT). Circulating leptin levels corrected for fat mass were lower in HF‐chow mice. Leptin administration was used to test whether reduced leptin level of HF‐chow mice inhibited further fat loss. Leptin treatment led to an additional reduction in adiposity. Finally, HF‐HF mice had lower mRNA levels of β₃ adrenergic receptor (β₃‐AR) in epididymal WAT (EWAT) compared to chow‐fed mice, and diet change led to an increase in the WAT β₃‐AR mRNA levels that were similar to the levels of chow‐fed mice, suggesting an elevation in sympathetic activation of WAT during diet switch relative to HF‐HF mice leading to the reduced leptin level and proinflammatory cytokine content. In summary, HF‐chow mice were resistant to further fat loss due to leptin insufficiency. Diet alteration from HF to low fat improved metabolic state of DIO mice, although their adiposity was defended at a higher level.     

CCAAT/enhancer binding protein β-deficiency enhances type 1 diabetic bone phenotype by increasing marrow adiposity and bone resorption

Bone loss in type 1 diabetes is accompanied by increased marrow fat, which could directly reduce osteoblast activity or result from altered bone marrow mesenchymal cell lineage selection (adipocyte vs. osteoblast). CCAAT/enhancer binding protein beta (C/EBPβ) is an important regulator of both adipocyte and osteoblast differentiation. C/EBPβ-null mice have delayed bone formation and defective lipid accumulation in brown adipose tissue. To examine the balance of C/EBPβ functions in the diabetic context, we induced type 1 diabetes in C/EBPβ-null (knockout, KO) mice. We found that C/EBPβ deficiency actually enhanced the diabetic bone phenotype. While KO mice had reduced peripheral fat mass compared with wild-type mice, they had 5-fold more marrow adipocytes than diabetic wild-type mice. The enhanced marrow adiposity may be attributed to compensation by C/EBPδ, peroxisome proliferator-activated receptor-γ2, and C/EBPα. Concurrently, we observed reduced bone density. Relative to genotype controls, trabecular bone volume fraction loss was escalated in diabetic KO mice (-48%) compared with changes in diabetic wild-type mice (-22%). Despite greater bone loss, osteoblast markers were not further suppressed in diabetic KO mice. Instead, osteoclast markers were increased in the KO diabetic mice. Thus, C/EBPβ deficiency increases diabetes-induced bone marrow (not peripheral) adipose depot mass, and promotes additional bone loss through stimulating bone resorption. C/EBPβ-deficiency also reduced bone stiffness and diabetes exacerbated this (two-way ANOVA P < 0.02). We conclude that C/EBPβ alone is not responsible for the bone vs. fat phenotype switch observed in T1 diabetes and that suppression of CEBPβ levels may further bone loss and decrease bone stiffness by increasing bone resorption.     

Methionine-Restricted C57BL/6J Mice Are Resistant to Diet-Induced Obesity and Insulin Resistance but Have Low Bone Density

Dietary methionine restriction (MR) extends lifespan, an effect associated with reduction of body weight gain, and improvement of insulin sensitivity in mice and rats as a result of metabolic adaptations in liver, adipose tissue and skeletal muscle. To test whether MR confers resistance to adiposity and insulin resistance, C57BL/6J mice were fed a high fat diet (HFD) containing either 0.86% methionine (control fed; CF) or 0.12% methionine (methionine-restricted; MR). MR mice on HFD had lower body weight gain despite increased food intake and absorption efficiency compared to their CF counterparts. MR mice on HFD were more glucose tolerant and insulin sensitive with reduced accumulation of hepatic triglycerides. In plasma, MR mice on HFD had higher levels of adiponectin and FGF21 while leptin and IGF-1 levels were reduced. Hepatic gene expression showed the downregulation of Scd1 while Pparg, Atgl, Cd36, Jak2 and Fgf21 were upregulated in MR mice on HFD. Restriction of growth rate in MR mice on HFD was also associated with lower bone mass and increased plasma levels of the collagen degradation marker C-terminal telopeptide of type 1 collagen (CTX-1). It is concluded that MR mice on HFD are metabolically healthy compared to CF mice on HFD but have decreased bone mass. These effects could be associated with the observed increase in FGF21 levels.     

Insulin secretion after dietary supplementation with conjugated linoleic acids and n-3 polyunsaturated fatty acids in normal and insulin-resistant mice

Conjugated linoleic acids (CLAs) and n-3 polyunsaturated fatty acids (PUFAs) improve insulin sensitivity in insulin-resistant rodents. However, the effects of these fatty acids on insulin secretion are not known but are of importance to completely understand their influence on glucose homeostasis. We therefore examined islet function after dietary supplementation consisting of 1% CLAs in combination with 1% n-3 enriched PUFAs for 12 wk to mice on a normal diet and to insulin-resistant mice fed a high-fat diet (58% fat). In the mice fed a normal diet, CLA/PUFA supplementation resulted in insulin resistance associated with low plasma adiponectin levels and low body fat content. Intravenous and oral glucose tolerance tests revealed a marked increase in insulin secretion, which nevertheless was insufficient to counteract the insulin resistance, resulting in glucose intolerance. In freshly isolated islets from mice fed the normal diet, both basal and glucose-stimulated insulin secretion were adaptively augmented by CLA/PUFA, and at a high glucose concentration this was accompanied by elevated glucose oxidation. In contrast, in high-fat-fed mice, CLA/PUFA did not significantly affect insulin secretion, insulin resistance, or glucose tolerance. It is concluded that dietary supplementation of CLA/PUFA in mice fed the normal diet augments insulin secretion, partly because of increased islet glucose oxidation, but that this augmentation is insufficient to counterbalance the induction of insulin resistance, resulting in glucose intolerance. Furthermore, the high-fat diet partly prevents the deleterious effects of CLA/PUFA, but this dietary supplementation was not able to counteract high-fat-diet-induced insulin resistance.     

Effects of Dietary Fatty Acids and Exercise on Body‐Weight Regulation and Metabolism in Rats

Objective: To assess the interaction of high‐fat diets (HF) made with different dietary fatty acids and exercise on body‐weight regulation, adiposity, and metabolism. Research Methods and Procedures: Male Wistar rats born to dams fed HF diets (40% w/w) made with either fish oil (FO), soybean oil (SO), or palm oil (PO) were fed diets similar to their dams and divided randomly into exercise (EX, swimming) or sedentary control (SD) groups when they were 9 weeks old. EX lasted for 6 weeks. Twenty‐four hours after the last EX bout, fasted rats were killed by decapitation. Chemical analyses and body composition analysis were conducted. Results: The results demonstrated that different fatty acids had different effects on body weight, composition, and metabolism. SO‐fed rats gained the most weight and fat. EX reduced body weight of FO‐ and PO‐fed rats, but SO‐fed rats were still heavier and fatter than other rats. Data from SO‐ and PO‐fed rats suggested that they are insulin resistant and that EX normalized this abnormality. Of the three HF diets used, FO produced the least adverse effects compared with PO and SO. Discussion: Not only the quantity of dietary fat, but also the type of fat used, will produce different effects on body weight and metabolism. EX ameliorates the suggested insulin resistance induced in rats fed either highly saturated or n‐6 polyunsaturated fatty acids. Long‐chain n‐3 polyunsaturated fatty acids, as found in fish oil, are more beneficial than n‐6 polyunsaturated fatty acids when fed in high amounts to rats.     

Macrophage TNF-alpha contributes to insulin resistance and hepatic steatosis in diet-induced obesity

Obesity is commonly associated with development of insulin resistance and systemic evidence of inflammation. Macrophages contribute to inflammatory amplification in obesity and may contribute directly to insulin resistance and the development of nonalcoholic fatty liver disease through the production of inflammatory cytokines, including tumor necrosis factor (TNF)-alpha. To test this hypothesis, we transplanted male wild-type (WT) and TNF-alpha deficient (KO) mice with either TNF-alpha-sufficient (TNF-alpha(+/+)) or TNF-alpha-deficient (TNF-alpha(-/-)) bone marrow. After consuming a high-fat diet for 26 wk, metabolic and morphometric characteristics of the animals were analyzed. While there were no differences in terms of relative weight gain, body composition analysis yielded a lower relative adipose and higher relative lean mass in mice lacking TNF-alpha, which was partially explained by reduced epididymal fat pad and liver weight. TNF-alpha(-/-) -->KO mice exhibited enhanced insulin sensitivity compared with that observed in TNF-alpha(+/+)-->KO mice; remarkably, no protection against insulin resistance was provided by transplanting TNF-alpha(-/-) bone marrow in WT mice compared with TNF-alpha(+/+)-->WT. The preserved insulin sensitivity seen in TNF-alpha(-/-)-->KO mice provided protection against the development of hepatic steatosis. Taken together, these data indicate that macrophage-derived TNF-alpha contributes to the pattern and extent of fat accumulation and insulin resistance in diet-induced obesity; however, this contribution is negligible in the presence of host-derived TNF-alpha.     

Metabolic effects of intra-abdominal fat in GHRKO mice

Mice with targeted deletion of the growth hormone receptor (GHRKO mice) are growth hormone (GH) resistant, small, obese, hypoinsulinemic, highly insulin sensitive and remarkably long-lived. To elucidate the unexpected coexistence of adiposity with improved insulin sensitivity and extended longevity, we examined effects of surgical removal of visceral (epididymal and perinephric) fat on metabolic traits related to insulin signaling and longevity. Comparison of results obtained in GHRKO mice and in normal animals from the same strain revealed disparate effects of visceral fat removal (VFR) on insulin and glucose tolerance, adiponectin levels, accumulation of ectopic fat, phosphorylation of insulin signaling intermediates, body temperature, and respiratory quotient (RQ). Overall, VFR produced the expected improvements in insulin sensitivity and reduced body temperature and RQ in normal mice and had opposite effects in GHRKO mice. Some of the examined parameters were altered by VFR in opposite directions in GHRKO and normal mice, and others were affected in only one genotype or exhibited significant genotype × treatment interactions. Functional differences between visceral fat of GHRKO and normal mice were confirmed by measurements of adipokine secretion, lipolysis, and expression of genes related to fat metabolism. We conclude that in the absence of GH signaling, the secretory activity of visceral fat is profoundly altered and unexpectedly promotes enhanced insulin sensitivity. The apparent beneficial effects of visceral fat in GHRKO mice may also explain why reducing adiposity by calorie restriction fails to improve insulin signaling or further extend longevity in these animals.     

Relationships of dietary fat, body composition, and bone mineral density in inbred mouse strain panels.

Laboratory inbred mouse strains show a broad range of variation in phenotypes, such as body composition, bone mineral density (BMD), plasma leptin, and insulin-like growth factor I (IGF-I), and thus provide a basis for the study of associations among them. We analyzed these phenotypes in male and female mice from 43 inbred strains fed on a high-fat (30% caloric content) diet and from 30 inbred strains fed on a low-fat (6%) diet. Structural equation modeling of these data reveals that the relationship of body fat content and areal BMD is altered by dietary factors and genotypes. Sex has no net effect on areal BMD, but after accounting for body mass difference females have higher areal BMD. Leptin is affected by relative fat mass and has no net effect on areal BMD. IGF-I has a direct effect on areal BMD.     

Glucose and lipid metabolism alterations in liver and adipose tissue pre-dispose p47phox knockout mice to systemic insulin resistance

Oxidative stress due to enhanced production or reduced scavenging of reactive oxygen species (ROS) has been associated with diet (dyslipidemia) induced obesity and insulin resistance (IR). The present study was undertaken to assess the role of p47^phox in IR using wild type (WT) and p47^phox?/? mice, fed with different diets (HFD, LFD or Chow). Augmented body weight, glucose intolerance and reduced insulin sensitivity were observed in p47^phox?/? mice fed with 45% HFD and 10% LFD. Further, body fat and circulating lipids were increased significantly with 5 weeks LFD feeding in p47^phox?/? mice, while parameters of energy homeostasis were reduced as compared with WT mice. LFD fed knockout (KO) mice showed an enhanced hepatic glycogenolysis, and reduced insulin signalling in liver and adipose tissue, while skeletal muscle tissue remained unaffected. A significant increase in hepatic lipids, adiposity, as well as expression of genes regulating lipid synthesis, breakdown and efflux were observed in LFD fed p47^phox?/? mice after 5 weeks. On the other hand, mice lacking p47^phox demonstrated altered glucose tolerance and tissue insulin sensitivity after 5 weeks chow feeding, while changes in body weight, respiratory exchange ratio (RER) and heat production are non-significant. Our data demonstrate that lack of p47^phox is sufficient to induce IR through altered glucose and lipid utilization by the liver and adipose tissue.     

trans-10,cis-12-Conjugated linoleic acid reduces leptin secretion from 3T3-L1 adipocytes

The trans10,cis12 (t10c12) isomer of conjugated linoleic acid (CLA) has been shown to inhibit heparin-releasable lipoprotein lipase activity, reduce lipid stores in cultured 3T3-L1 adipocytes, and, when fed to mice, reduce body fat gain. We now report that t10c12 CLA significantly reduced leptin secretion from cultured 3T3-L1 adipocytes, and reduced leptin mRNA levels within the cells. Similar effects were produced by conjugated nonadecadienoic acid (a 19-carbon CLA cognate that is more effective than CLA in reducing body fat gain in mice), the lipoxygenase inhibitor nordihydroguaiaretic acid (which is synergistic with CLA in reducing body fat gain in mice), and ciglitazone (TZD, a PPARgamma agonist). Feeding mice diet supplemented with 0.5% t10c12 CLA for 4 weeks significantly reduced body fat gain, serum leptin levels and adipocyte leptin mRNA expression, without affecting feed intake or body weight. These data provide new insights into apparent mechanistic similarities among t10c12 CLA, CNA, NDGA, and TZD.