The Development of Diet-Induced Obesity and Glucose Intolerance in C57Bl/6 Mice on a High-Fat Diet Consists of Distinct Phases

Background and Hypothesis: Camurati-Engelmann Disease (CED) is characterized by extreme bone turnover and excess TGF-β release. We previously showed that bone-derived TGF-β causes glucose intolerance, increases skeletal muscle weakness, and exacerbates diet-induced obesity in CED mice. However, it is unknown whether glucose intolerance and obesity alter bone and muscle phenotypes. Thus, we hypothesized that impaired glucose metabolism and diet-induced obesity exacerbate bone and muscle loss in a mouse model of CED. Experimental Design: 45-week WT and CED mice were fed either high-fat diet (HFD) or low-fat diet (LFD) for 15 weeks. Ex vivo bone micro-CT and histomorphometry were used to evaluate bone and muscle. Statistical analysis was performed using GraphPad Prism with p<0.05 considered significant. Results: CED mice showed severe cortical and trabecular bone loss in response to diet-induced obesity. Trabecular bone volume was reduced by 37% in L5 vertebrae (p<0.001), 16% in tibiae (p<0.05), and 7% in femora in CED-HFD compared to WT-HFD. Bone mineral density was reduced (p<0.0001) and cortical porosity was increased (p<0.0001) in CED-HFD vs WT-HFD in femora and tibiae. Bone histomorphometry showed no significant differences in osteoclast number between groups. pSMAD2/3 staining was increased by 25% (p<0.05) and muscle fiber diameter was reduced by 32% (p<0.05) in the tibialis anterior muscle of CED mice compared to WT, with greater changes in HFD-fed mice. Conclusion and Potential Impact: High-fat diet and impaired glucose metabolism exacerbates bone loss and increases TGF-β signaling in CED mice. In future studies, inhibiting TGF-β signaling and reducing adiposity may prevent glucose intolerance and musculoskeletal deterioration in conditions of high bone turnover.

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Differentially Regulated Protein Kinase A (PKA) Activity in Adipose Tissue and Liver Is Associated With Resistance to Diet-Induced Obesity and Glucose Intolerance in Mice That Lack PKA Regulatory Subunit Type IIα

Endocrinology ◽

10.1210/en.2014-1122 ◽

2014 ◽

Vol 155 (9) ◽

pp. 3397-3408 ◽

Cited By ~ 17

Author(s):

Edra London ◽

Maria Nesterova ◽

Ninet Sinaii ◽

Eva Szarek ◽

Tatyana Chanturiya ◽

...

Keyword(s):

Adipose Tissue ◽

Protein Kinase ◽

Glucose Intolerance ◽

High Fat Diet ◽

Regulatory Subunit ◽

Wild Type ◽

High Fat ◽

Diet Induced Obesity ◽

Pka Regulatory Subunit ◽

Kinase A

Abstract The cAMP-dependent protein kinase A (PKA) signaling system is widely expressed and has a central role in regulating cellular metabolism in all organ systems affected by obesity. PKA has four regulatory (RIα, RIIα, RIβ, RIIβ) and four catalytic (Cα, Cβ, Cγ, Prkx) subunit isoforms that have tissue-specific expression profiles. In mice, knockout (KO) of RIIβ, the primary PKA regulatory subunit in adipose tissue or knockout of the catalytic subunit Cβ resulted in a lean phenotype that resists diet-induced obesity and associated metabolic complications. Here we report that the disruption of the ubiquitously expressed PKA RIIα subunit in mice (RIIαKO) confers resistance to diet-induced obesity, glucose intolerance, and hepatic steatosis. After 2-week high-fat diet exposure, RIIαKO mice weighed less than wild-type littermates. Over time this effect was more pronounced in female mice that were also leaner than their wild-type counterparts, regardless of the diet. Decreased intake of a high-fat diet contributed to the attenuated weight gain in RIIαKO mice. Additionally, RIIα deficiency caused differential regulation of PKA in key metabolic organs: cAMP-stimulated PKA activity was decreased in liver and increased in gonadal adipose tissue. We conclude that RIIα represents a potential target for therapeutic interventions in obesity, glucose intolerance, and nonalcoholic fatty liver disease.

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