Obesity of TallyHO/JngJ Mouse Is Due to Increased Food Intake with Early Development of Leptin Resistance

Rhee, Sang Dal; Sung, Yonghun; Lee, Y. S.; Kim, J. Y.; Jung, Won Hoon; Kim, M. J.; Lee, M.-S.; Lee, M. K.; Yang, Sungchil; Cheon, Hyae Gyeong

doi:10.1055/s-0030-1267202

Cited by 16 publications

(17 citation statements)

References 29 publications

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“…When pair fed with C57Bl6/J mice, the Tallyho mice have the same rate of weight gain as the C57Bl6/J mice. Furthermore, the authors show that Tallyho mice have hypothalamic leptin resistance and upregulation of NPY mRNA levels [87] . There are, to the best of our knowledge, no publications in which Tallyho mice have been used in the pharmacological treatment of obesity; therefore, their utility and predictivity for human obesity treatment is unclear.…”

Section: Tallyho Mousementioning

confidence: 99%

Laboratory animals as surrogate models of human obesity

Nilsson¹,

Raun²,

Yan³

et al. 2012

Acta Pharmacol Sin

240

104

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Obesity and obesity-related metabolic diseases represent a growing socioeconomic problem throughout the world. Great emphasis has been put on establishing treatments for this condition, including pharmacological intervention. However, there are many obstacles and pitfalls in the development process from pre-clinical research to the pharmacy counter, and there is no certainty that what has been observed pre-clinically will translate into an improvement in human health. Hence, it is important to test potential new drugs in a valid translational model early in their development. In the current mini-review, a number of monogenetic and polygenic models of obesity will be discussed in view of their translational character.Keywords: obesity; animal models; sibutramine; liraglutide; KK-A y mice; ob/ob mice; Zucker rat; diet-induced obesity models Acta Pharmacologica Sinica (2012) 33: 173-181; doi: 10.1038/aps.2011 Review IntroductionAs the prevalence of obesity is rising along with its socioeconomic consequences, the quest to find new treatments or a cure is also increasing (http://www.who.int/mediacentre/ factsheets/fs311/en/). Pharmaceutical treatment is one avenue that has been pursued, but currently there are only a limited number of compounds on the market because many have failed or been withdrawn because of side effects. Given that the development process from initial idea to marketed product typically requires more than 10 years and the attrition rate is notably high, it is important that the models used, whether in vitro or in vivo, are good surrogates for human obesity. Depending on the target in question, there are a number of models that can be applied. In the following pages, we will review the most widely used animal models in obesity research. We have categorized the different models into groups; rodent models are divided into monogenetic, polygenetic, and selectively bred diet-induced obesity (DIO) models, and finally we discuss the DIO pig model. To demonstrate the translational potential of the selected models, we have chosen two different model compound families that have been tested in human cohorts -sibutramine and liraglutide or other glucagon-like peptide-1 (GLP)-1 analogues [1 , 2] . Sibutramine is a serotonin and norepinephrine re-uptake inhibitor that was developed for the treatment of obesity and has been on the market for the past 9 years, although in most markets it has been withdrawn because of undesirable side effects [3] . Liraglutide is a GLP-1 analogue currently in phase 3 clinical development for severe obesity after demonstrating positive results in phase 2 trials [2] . By choosing the best suited animal model for a particular study, it is possible to make a qualified assessment as to whether target X and/or compound Y will have an impact in clinical practice at a much earlier point. Monogenic modelsKK-A y mice The inbred mouse strain KK was established in Japan and is a mouse model with peripheral insulin sensitivity and glucose intolerance [4] . Insulin resistance in the KK mouse i...

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Section: Tallyho Mousementioning

confidence: 99%

Laboratory animals as surrogate models of human obesity

Nilsson¹,

Raun²,

Yan³

et al. 2012

Acta Pharmacol Sin

240

104

View full text Add to dashboard Cite

show abstract

“…Another commercially available, polygenic, spontaneous mouse model for T2D is the TallyHO strain. This mouse develops hyperglycemia before skeletal maturity [35] and is obese compared to its recommended control strain, SWR/J [36, 37]. As previously reported by Devlin et al, the femur diaphysis is structurally stronger in bending but brittle (lower post-yield displacement) for the diabetic TallyHO compared to non-diabetic SWR mice at 17 weeks of age [36].…”

Section: Introductionmentioning

confidence: 97%

Low bone toughness in the TallyHO model of juvenile type 2 diabetes does not worsen with age

Creecy

Uppuganti

Ünal

et al. 2018

Bone

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Fracture risk increases as type 2 diabetes (T2D) progresses. With the rising incidence of T2D, in particular early-onset T2D, a representative pre-clinical model is needed to study mechanisms for treating or preventing diabetic bone disease. Towards that goal, we hypothesized that fracture resistance of bone from diabetic TallyHO mice decreases as the duration of diabetes increases. Femurs and lumbar vertebrae were harvested from male, TallyHO mice and male, non-diabetic SWR/J mice at 16weeks (n≥12 per strain) and 34weeks (n≥13 per strain) of age. As is characteristic of this model of juvenile T2D, the TallyHO mice were obese and hyperglycemic at an early age (5weeks and 10weeks of age, respectively). The femur mid-shaft of TallyHO mice had higher tissue mineral density and larger cortical area, as determined by micro-computed tomography, compared to the femur mid-shaft of SWR/J mice, irrespective of age. As such, the diabetic rodent bone was structurally stronger than the non-diabetic rodent bone, but the higher peak force endured by the diaphysis during three-point (3pt) bending was not independent of the difference in body weight. Upon accounting for the structure of the femur diaphysis, the estimated toughness at 16weeks and 34weeks was lower for the diabetic mice than for non-diabetic controls, but neither toughness nor estimated material strength and resistance to crack growth (3pt bending of contralateral notched femur) decreased as the duration of hyperglycemia increased. With respect to trabecular bone, there were no differences in the compressive strength of the L6 vertebral strength between diabetic and non-diabetic mice at both ages despite a lower trabecular bone volume for the TallyHO than for the SWR/J mice at 34weeks. Amide I sub-peak ratios as determined by Raman Spectroscopy analysis of the femur diaphysis suggested a difference in collagen structure between diabetic and non-diabetic mice, although there was not a significant difference in matrix pentosidine between the groups. Overall, the fracture resistance of bone in the TallyHO model of T2D did not progressively decrease with increasing duration of hyperglycemia. However, given the variability in hyperglycemia in this model, there were correlations between blood glucose levels and certain structural properties including peak force.

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“…Effect of obesity on Cl-HCO 3 exchange in intestinal epithelial cells. DIDS-sensitive and HCO 3 -driven 36 Cl uptake was significantly increased in villus-cell BBMVs of OZRs as compared with LZRs (A), TOM vs. C57BL/6 (B), and obese human small intestine vs. normal (C ). For all experiments, n represents different studies performed with intestinal cells isolated from different host each time; n = 4.…”

Section: Discussionmentioning

confidence: 99%

“…Briefly, cells were incubated for 10 min in gluconate buffer containing 115 mM Na gluconate, 5 mM K-gluconate, 25 mM NaHCO 3 , and 20 mM Tris-HEPES (pH 7.5) at room temperature. Uptake was initiated by the addition of the reaction medium containing 115 mM Na gluconate, 5 mM K-gluconate, 4 mM NaHCO 3 , 20 mM Tris-MES (pH 5.5), 5 mM NMG, and 2.5 mM HCl with 36 HCl in the presence or absence of 1 mM DIDS. 36 Cl uptake was arrested at 2 min, and the cells were washed with icecold gluconate buffer and processed as previously described.…”

Section: Uptake Studies In Iec-18 Cellsmentioning

confidence: 99%

Inhibition of intestinal villus cell Na/K‐ATPase mediates altered glucose and NaCl absorption in obesity‐associated diabetes and hypertension

et al. 2019

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During obesity, diabetes and hypertension inevitably coexist and cause innumerable health disparities. In the obesity, diabetes, and hypertension triad (ODHT), deregulation of glucose and NaCl homeostasis, respectively, causes diabetes and hypertension. In the mammalian intestine, glucose is primarily absorbed by Naglucose cotransport 1 (SGLT1) and coupled NaCl by the dual operation of Na‐H exchange 3 (NHE3) and Cl‐HCO3 [down‐regulated in adenoma (DRA) or putative anion transporter 1 (PAT1)] exchange in the brush border membrane (BBM) of villus cells. The basolateral membrane (BLM) Na/K‐ATPase provides the favorable transcellular Na gradient for BBM SGLT1 and NHE3. How these multiple, distinct transport processes may be affected in ODHT is unclear. Here, we show the novel and broad regulation by Na/K‐ATPase of glucose and NaCl absorption in ODHT in multiple species (mice, rats, and humans). In vivo, during obesity inhibition of villus‐cell BLM, Na/K‐ATPase led to compensatory stimulation of BBM SGLT1 and DRA or PAT1, whereas NHE3 was unaffected. Supporting this new cellular adaptive mechanism, direct silencing of BLM Na/K‐ATPase in intestinal epithelial cells resulted in selective stimulation of BBM SGLT1 and DRA or PAT1 but not NHE3. These changes will lead to an increase in glucose absorption, maintenance of traditional coupled NaCl absorption, and a de novo increase in NaCl absorption from the novel coupling of stimulated SGLT1 with DRA or PAT1. Thus, these novel observations provide the pathophysiologic basis for the deregulation of glucose and NaCl homeostasis of diabetes and hypertension, respectively, during obesity. These observations may lead to more efficacious treatment for obesity‐associated diabetes and hypertension.—Palaniappan, B., Arthur, S., Sundaram, V. L., Butts, M., Sundaram, S., Mani, K., Singh, S., Nepal, N., Sundaram, U. Inhibition of intestinal villus cell Na/K‐ATPase mediates altered glucose and NaCl absorption in obesity‐associated diabetes and hypertension. FASEB J. 33, 9323–9333 (2019). http://www.fasebj.org

show abstract

Obesity of TallyHO/JngJ Mouse Is Due to Increased Food Intake with Early Development of Leptin Resistance

Cited by 16 publications

References 29 publications

Laboratory animals as surrogate models of human obesity

Laboratory animals as surrogate models of human obesity

Low bone toughness in the TallyHO model of juvenile type 2 diabetes does not worsen with age

Inhibition of intestinal villus cell Na/K‐ATPase mediates altered glucose and NaCl absorption in obesity‐associated diabetes and hypertension

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