Genotype-dependent Metabolic Responses to Semi-Purified High-Sucrose High-Fat Diets in the TALLYHO/Jng vs. C57BL/6 Mouse during the Development of Obesity and Type 2 Diabetes

Abstract

The co-epidemic of obesity and type 2 diabetes is associated with increased morbidity and mortality. Genetic factors are highly involved in the development of these diseases, in the form of interactions of multiple genes within obesogenic and diabetogenic environments, such as a high fat diet. The TALLYHO/Jng (TH) mouse is an inbred polygenic model for human obesity and type 2 diabetes. In order to further develop the TH mouse as a clinically relevant model, we investigated diet dependence of obesity and type 2 diabetes in TH mice vs. C57BL/6 (B6) mice. TH and B6 mice were weaned onto a standard rodent chow, semi-purified high-sucrose low-fat (HSLF), or semi-purified high-sucrose high-fat (HSHF) diet and maintained on these diets throughout the study. Despite similar fat contents in HSLF diets and chow, both B6 and TH mice responded to HSLF diets, with increases in adiposity. TH mice, but not B6 mice, exhibited significantly higher adiposity with severely aggravated glucose intolerance and hyperglycemia on HSHF diets compared to the other diets. HSLF diets also advanced diabetes in TH mice compared to chow, but it did not surpass the effects of HSHF diets. The severe glucose intolerance and hyperglycemia in TH mice on both HSLF and HSHF diets were accompanied by significantly reduced mRNA levels compared to B6 mice. The present data demonstrate that diets are important modulators of genetic susceptibility to type 2 diabetes and obesity in TH mice. The interplay between heredity and dietary environment in TH mice appears to amplify insulin resistance, contributing to severe glucose intolerance and diabetes.

Congenic mice demonstrate the presence of QTLs conferring obesity and hypercholesterolemia on chromosome 1 in the TALLYHO mouse

“…Energy expenditure determined by heat production normalized with body weight (kcal/kg/hr) was lower in B6.TH-Chr1-128Mb congenic mice than B6 mice. These findings are consistent with the characterization of parental TH strain (Parkman et al 2016). …”

A Diabetic Mice Model For Studying Skin Wound Healing

“…Usually mice models with severe diabetes, develop such condition early in life, thus, the important component of aging is missing (7)(8)(9). Conversely, in models of DM induced by the consumption of energy dense diets lead to a chronic condition that can be sustained until late life; however, under these circumstances, metabolic abnormalities are generally mild (34)(35)(36).…”

“…Usually mice models with severe diabetes, develop such condition early in life, thus, the important component of aging is missing (7–9). Previous models of DM induced by the consumption of energy dense diets showed chronic conditions that can be sustained until late life; however, metabolic abnormalities are generally mild (34–36). Here, we described a mouse model that enhances metabolic severity (pharmacological-induced DM) to the aging process occurring on a long-term HFD feeding.…”

An older diabetes-induced mice model for studying skin wound healing

“…Usually mice models with severe diabetes, develop such condition early in life, thus, the important component of aging is missing [12][13][14]. Conversely, in models of DM induced by the consumption of energy dense diets lead to a chronic condition that can be sustained until late life; however, under these circumstances, metabolic abnormalities are generally mild [41][42][43].…”