Can Exercise Ameliorate Memory Impairment via PPAR Gamma Activation in Rats Fed A High-Fat Diet?

Abstract Objectives Obesity is detrimental to bone health in humans and in high-fat diet-induced obese animals. Bone marrow osteoblasts and adipocytes are derived from a common mesenchymal stem cell and have a reciprocal relationship. Peroxisome proliferator-activated receptor gamma (PPAR gamma), a regulator for adipocyte differentiation, may be a potential target for reducing obesity and increasing bone mass. This study tested the hypothesis that bone-specific PPAR gamma conditional knockout (cKO), via deletion of PPAR gamma gene from bone marrow stromal cells (BMSC) using Osterix 1 (Osx1)-Cre, would prevent high-fat diet-induced bone deterioration in mice. Methods PPAR gamma cKO (PPAR gammafl/fl: Osx1–Cre) and floxed littermate control (PPAR gammafl/fl Osx1-P-Cre-) mice at 6-wk-old were randomly assigned to 4 groups (n = 12/group, 6 male and 6 female) and fed ad libitum either a normal-fat purified diet (NF, 3.85 kcal/g, 10% energy as fat) or a high-fat diet (HF, 4.73 kcal/g) for 6 mo. Bone structure, body composition, and serum bone-related cytokines were measured. Results Compared to the NF diet, the HF diet increased body mass and fat mass (P < 0.05) but not lean mass. The HF diet also decreased tibial and lumbar vertebrae trabecular volume/total volume (BV/TV) and bone mineral density (BMD) in both control and PPAR gamma cKO mice. PPAR gamma cKO mice had lower body fat mass and lean mass than control mice. PPAR gamma cKO mice had greater tibial trabecular BV/TV, trabecular number, connectivity density, and BMD and lower structure model index, compared to control mice. None of trabecular bone parameters at 2nd lumbar vertebrae was affected by genotype. PPAR gamma cKO mice had lower cortical medullary area, compared to control mice. PPAR gamma cKO mice had lower (P < 0.01) serum concentration of leptin and higher (P < 0.05) concentration of osteocalcin, compared with control mice. Conclusions These data indicate that PPAR gamma has site-specific impact on bone structure in mice and that knockout PPAR gamma in BMSC increased bone mass in tibia likely through increased osteoblastogenesis. However, PPAR gamma disruption in BMSC did not prevent high-fat diet-induced bone deterioration in mice. Funding Sources USDA-ARS #3062-51,000-053-00D.

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Endothelin-1 Receptor A Blockade Attenuates Metabolic and Proinflammatory Profile in Mice Fed a High Fat Diet

Journal of the Endocrine Society ◽

10.1210/jendso/bvab048.081 ◽

2021 ◽

Vol 5 (Supplement_1) ◽

pp. A41-A42

Author(s):

Osvaldo Rivera-Gonzalez ◽

Erin Taylor ◽

Joshua S Speed

Keyword(s):

Insulin Resistance ◽

Adipose Tissue ◽

Visceral Adipose Tissue ◽

High Fat Diet ◽

Immune Cell ◽

Ppar Gamma ◽

High Fat ◽

Endothelin 1 ◽

Eta Receptor ◽

Visceral Adipose

Abstract Endothelin-1 (ET-1) is elevated in patients with obesity; however, its contribution to the pathophysiology related to obesity is not fully understood. Obesity is associated with dyslipidemia and insulin resistance, which may in part be mediated by inflammation and alterations to immune cell subsets within the adipose tissue. ET-1 promotes inflammation via the ET-1 type A (ETA) receptor, and blockade of ETA receptors improves dyslipidemia in patients with chronic kidney disease. We hypothesized that ET-1 causes dyslipidemia and inflammation within the adipose tissue of obese mice. To test this hypothesis, C57BL/6J mice were fed either normal diet (NMD) or high fat diet (HFD) for 8 weeks followed by 2 weeks of treatment with either vehicle or atrasentan (ETA receptor antagonist, 10mg/kg/day). HFD mice had significantly higher fat mass than NMD mice, with no significant effect of treatment with atrasentan. HFD mice had significantly higher circulating non-esterified free fatty acids, an effect that was ameliorated in mice treated with atrasentran (1.03±0.07 vs 0.58±0.02 mEq/L, p<0.05). Atrasentan-treated mice had significantly attenuated increase in liver triglycerides compared to non-treated HFD mice (3.8±0.7 vs 7.5±1.3mg/dL respectively, p<0.05). Mice treated with atrasentan had significantly improved glucose tolerance (10150±1031 vs 6563±975 AUC, p<0.05) and insulin tolerance (-2796±386 vs -9825±319 AUC, p<0.05) compared to non-treated insulin-resistant HFD mice. Plasma adiponectin, an insulin sensitizing adipokine that is inversely associated with adiposity and insulin resistance, was significantly increased in atrasentan-treated mice compared to non-treated HFD (4.8±0.1326 vs 6.5±0.3 µg/ml, p<0.05), with no differences in plasma insulin levels. Gene expression analysis of visceral fat showed improved expression of genes negatively associated with insulin resistance that were downregulated in non-treated HFD mice vs. NMD (IRS-1, PPAR-gamma, GLUT4, and adiponectin). Flow cytometric analyses of visceral adipose tissue indicated that HFD mice had a significantly higher number of both CD4+ and CD8+ T cells compared to NMD mice, which was attenuated by treatment with atrasentan. Further, eosinophils, which are important in maintaining adipose tissue health and reducing inflammation, were significantly decreased in HFD mice compared to NMD. Atrasentan treatment abolished the decrease in eosinophils. Taken together, these data indicate that ETA receptor blockade improves peripheral glucose homeostasis, dyslipidemia, and liver triglyceride levels, and also attenuates the proinflammatory immune profile in visceral adipose tissue. These data suggest a potential use for ETA receptor blockers in the treatment of obesity-associated dyslipidemia and insulin resistance.

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Effects of post-training administration of LY341495, as a mGluR2/3 antagonist on spatial memory deficit in rats fed with high-fat diet

10.21203/rs.2.22325/v1 ◽

2020 ◽

Author(s):

Heresh Moridi ◽

Abdolrahman Sarihi ◽

Elahe Habibitabar ◽

Hossein Shateri ◽

Iraj Salehi ◽

...

Keyword(s):

Spatial Memory ◽

High Fat Diet ◽

Memory Impairment ◽

Metabotropic Glutamate Receptors ◽

Reference Memory ◽

Memory Deficit ◽

Male Rats ◽

High Fat ◽

Target Zone ◽

Spatial Memory Deficit

Abstract Background High-fat diets (HFDs) adversely influence glutamate metabolism and neurotransmission. The precise role of the group II metabotropic glutamate receptors (mGluR2/3) antagonist on spatial memory deficit following consumption of HFD has not yet been clarified. Therefore, in this study, we examined the effects of post-training administration of mGluR2/3 antagonism; LY341495 on spatial memory in rats fed with HFD by using Morris Water Maze (MWM) task. Intraperitoneal injection (i.p) injection of LY341495 was done 30 minutes before retention test. Results Our results showed that HFD did not have any effect on memory acquisition. There were not significant differences in escape latency and swimming distance between experimental groups (P>0.05, Two-way ANOVA). Our finding showed that consumption of an HFD leads to spatial memory impairment. There were significant differences in time spent in target zone between experimental groups [F (3, 20) = 7.031, P=0.0021, one-way ANOVA]. Also, LY341495 improved HFD-induced reference memory impairment. HFD animals treated with LY341495 spent more time in the target zone in compare with HFD animals (P= 0.0449). Conclusions Our results suggested that prolonged consumption of high-fat diet has no effects on the acquisition of spatial learning, but can impair memory retention of the adult male rats and post-training administration of LY341495 can improve HFD-induced reference memory impairment.

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