Altered IGF-I activity and accelerated bone elongation in growth plates precedes excess weight gain in a mouse model of juvenile obesity

Author(s):  
Allison L. Machnicki ◽  
Cassaundra A. White ◽  
Chad A. Meadows ◽  
Darby McCloud ◽  
Sarah Evans ◽  
...  

Nearly one-third of children in the United States are overweight or obese by their pre-teens. Tall stature and accelerated bone elongation are characteristic features of childhood obesity, which co-occur with conditions such as limb bowing, slipped epiphyses, and fractures. Obese children paradoxically have normal circulating IGF-I, the major growth-stimulating hormone. Here we describe and validate a mouse model of excess dietary fat to examine mechanisms of growth acceleration in obesity. We used in vivo multiphoton imaging and immunostaining to test the hypothesis that high-fat diet increases IGF-I activity and alters growth plate structure before the onset of obesity. We tracked bone and body growth in male and female C57BL/6 mice (N = 114) on high-fat (60% kcal fat) or control (10% kcal fat) diets from weaning (3-weeks) to skeletal maturity (12-weeks). Tibial and tail elongation rates increased after brief (1-2 week) high-fat diet exposure without altering serum IGF-I. Femoral bone density and growth plate size were increased, but growth plates were disorganized in not-yet-obese high-fat diet mice. Multiphoton imaging revealed more IGF-I in the vasculature surrounding growth plates of high-fat diet mice, and increased uptake when vascular levels peaked. High-fat diet growth plates had more activated IGF-I receptors and fewer inhibitory binding proteins, suggesting increased IGF-I bioavailability in growth plates. These results, which parallel pediatric growth patterns, highlight the fundamental role of diet in the earliest stages of developing obesity-related skeletal complications and validate the utility of the model for future studies aimed at determining mechanisms of diet-enhanced bone lengthening.

Stroke ◽  
2012 ◽  
Vol 43 (suppl_1) ◽  
Author(s):  
Sean S Li ◽  
Amy K Guzik ◽  
Brian H Annex ◽  
Bradford B Worrall

Background: Stroke is a leading cause of serious long-term adult disability in the United States. Hyperglycemia has consistently been associated with worse clinical outcomes from ischemic stroke. Animal studies utilizing genetic models of type II diabetes have shown greater ischemic injury in the setting of hyperglycemia. However, these models may not well represent all physiological aspects of human type II diabetes and post-stroke hyperglycemia. Diet induced diabetes may prove more analogous to human disease. The high fat diet mouse model of type II diabetes reliably creates a subacute hyperglycemic state. We evaluated normal and high fat diet (HFD) fed mice following middle cerebral artery occlusion (MCAO) to determine if post-ischemic functional status is influenced by hyperglycemia in this model. Methods: C57BL/6 male mice (12-18 weeks) fed either normal diet or HFD (60%kCal fat) were subjected to 60 minutes of transient MCAO via 6-0 monofilament. Triphenyltetrazolium chloride staining confirmed infarction in a subset of mice. A glucose tolerance test was performed, and fasting blood sugar was tested prior to surgery to verify hyperglycemia. Neurologic deficit score (NDS) was measured before and after surgery, and 24 hours post MCAO. Results: HFD fed mice demonstrated worse NDS following ischemia compared to normal fed mice. This was significant at 24 hours post MCAO (p<0.0001). Normal fed mice showed improvement in functional score 24 hours post MCAO (p<0.05), but HFD fed mice demonstrated no improvement. Conclusion: Our data show that HFD fed mice have worse outcomes post-MCAO and without the recovery in functional scores seen in normal fed mice. This mirrors the human condition, where worse clinical outcomes are seen in hyperglycemic patients with ischemic stroke. This model provides an opportunity to investigate mechanisms underlying differential recovery in the setting of hyperglycemia and to test if insulin treatment can prevent the adverse recovery in HFD animals as has been postulated in humans. We are conducting gene expression experiments to test candidates that may mediate ischemic damage and recovery and to identify novel therapeutic targets.


2020 ◽  
Vol 34 (S1) ◽  
pp. 1-1
Author(s):  
Allison L. Machnicki ◽  
Cassaundra A. Song ◽  
Sarah Evans ◽  
Chad A. Meadows ◽  
Darby McCloud ◽  
...  

2019 ◽  
Vol 33 (S1) ◽  
Author(s):  
Maria A Serrat ◽  
Allison L Machnicki ◽  
Chad A Meadows ◽  
Darby McCloud ◽  
Dominic Thomas ◽  
...  

Author(s):  
Alejandra Freire Fernández-Regatillo ◽  
María L. de Ceballos ◽  
Jesús Argente ◽  
Sonia Díaz Pacheco ◽  
Clara González Martínez

2015 ◽  
Vol 44 (8) ◽  
pp. 1105-1113
Author(s):  
Hyelin Jeon ◽  
Sungmin Kwak ◽  
Su-Jin Oh ◽  
Hyun Soo Nam ◽  
Doo Won Han ◽  
...  

Molecules ◽  
2021 ◽  
Vol 26 (2) ◽  
pp. 302
Author(s):  
Ahtesham Hussain ◽  
Jin Sook Cho ◽  
Jong-Seok Kim ◽  
Young Ik Lee

Background: Currently, obesity is a global health challenge due to its increasing prevalence and associated health risk. It is associated with various metabolic diseases, including diabetes, hypertension, cardiovascular disease, stroke, certain forms of cancer, and non-alcoholic liver diseases (NAFLD). Objective: The aim of this study to evaluate the effects of polyphenol enriched herbal complex (Rubus crataegifolius/ellagic acid, Crataegus pinnatifida Bunge/vitexin, chlorogenic acid, Cinnamomum cassiaa/cinnamic acid) on obesity and obesity induced NAFLD in the high-fat diet (HFD)-induced obese mouse model. Methods: Obesity was induced in male C57BL/6 mice using HFD. After 8 weeks, the mice were treated with HFD+ plants extract for 8 weeks. Body weight, food intake weekly, and blood sugar level were measured. After sacrifice, changes in the treated group’s liver weight, fat weight, serum biochemical parameters, hormone levels, and enzyme levels were measured. For histological analysis, tissues were stained with hematoxylin-eosin (H&E) and Oil Red-O. Results: Our results showed that the herbal complex ameliorated body weight and liver weight gain, and decreased total body fat in HFD-fed animals. Post prandial blood glucose (PBG) and fasting blood glucose (FBG) were lower in the herbal complex-treated group than in the HFD control group. Additionally, herbal formulation treatment significantly increased HDL levels in serum and decreased TC, TG, AST, ALT, deposition of fat droplets in the liver, and intima media thickness (IMT) in the aorta. Herbal complex increased serum adiponectin and decreased serum leptin. Herbal complex also increased carnitine palmityl transferase (CPT) activity and significantly decreased enzyme activity of beta-hydroxy beta methyl glutamyl-CoA (HMG-CoA) reductase, and fatty acid synthase (FAS). Conclusions: The results of this study demonstrated that the herbal complex is an effective herbal formulation in the attenuation of obesity and obesity-induced metabolic dysfunction including NAFLD in HFD-induced mouse model.


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