Leptin- and Leptin Receptor-Deficient Rodent Models: Relevance for Human Type 2 Diabetes

Abstract

Among the most widely used animal models in obesity-induced type 2 diabetes mellitus (T2DM) research are the congenital leptin- and leptin receptor-deficient rodent models. These include the leptin-deficient ob/ob mice and the leptin receptor-deficient db/db mice, Zucker fatty rats, Zucker diabetic fatty rats, SHR/N-cp rats, and JCR:LA-cp rats. After decades of mechanistic and therapeutic research schemes with these animal models, many species differences have been uncovered, but researchers continue to overlook these differences, leading to untranslatable research. The purpose of this review is to analyze and comprehensively recapitulate the most common leptin/leptin receptor-based animal models with respect to their relevance and translatability to human T2DM. Our analysis revealed that, although these rodents develop obesity due to hyperphagia caused by abnormal leptin/leptin receptor signaling with the subsequent appearance of T2DM-like manifestations, these are in fact secondary to genetic mutations that do not reflect disease etiology in humans, for whom leptin or leptin receptor deficiency is not an important contributor to T2DM. A detailed comparison of the roles of genetic susceptibility, obesity, hyperglycemia, hyperinsulinemia, insulin resistance, and diabetic complications as well as leptin expression, signaling, and other factors that confound translation are presented here. There are substantial differences between these animal models and human T2DM that limit reliable, reproducible, and translatable insight into human T2DM. Therefore, it is imperative that researchers recognize and acknowledge the limitations of the leptin/leptin receptor-based rodent models and invest in research methods that would be directly and reliably applicable to humans in order to advance T2DM management.

High-Fat Diet–Induced Obesity Enhances Allograft Rejection

“…The genetic models comprise mice that are deficient in the leptin/leptin receptor axis and become obese from hyperphagia 29 , whereas the HFDmediated obese mice have increased leptin levels (data not shown) and do not display hyperphagia but rather have calorie-rich diet-induced weight gain. We used male C57BL/6 mice subjected to a HFD because they have been reported to develop obesity, hyperinsulinemia, hyperglycemia and hypertension that mimic the metabolic syndrome observed in patients with inflammatory obesity, whereas other mouse strains are more resistant to these effects 20 .…”

Activation of ERK1/2 Ameliorates Liver Steatosis in Leptin Receptor–Deficient (db/db) Mice via Stimulating ATG7-Dependent Autophagy

“…9). ERK1/2 is possibly activated in liver of young db/db and HFD mice, as insulin activates ERK1/2 (41) and serum insulin increases during this period (42). However, ERK1/2 may become inactivated in elder mice and result in decreasing hepatocyte proliferation.…”

Metabolic Syndrome and Diabetic Experimental Animal Models

“…Tip 2 DM araştırmalarında en yaygın kullanılan hayvan modelleri arasında bozulmuş leptin sinyal yoluna (konjenital leptin ve leptin reseptörü yetersizliği) sahip yaygın kullanılan üç monogenik obezite mo- deli (Lep ob/ob fare, Lepr db/db fare ve ZDF sıçan) bulunmaktadır. 63 Lep ob/ob fare, leptin geninde resesif bir mutasyon taşımakta ve bu mutasyon hiperfaji, obezite ve hiperglisemiye neden olmaktadır. [62][63][64] Artan vücut ağırlığı hiperinsülineminin ortaya çıkması ile (yaklaşık 2. hafta) açıkça görülmekte-dir.…”

“…63 Lep ob/ob fare, leptin geninde resesif bir mutasyon taşımakta ve bu mutasyon hiperfaji, obezite ve hiperglisemiye neden olmaktadır. [62][63][64] Artan vücut ağırlığı hiperinsülineminin ortaya çıkması ile (yaklaşık 2. hafta) açıkça görülmekte-dir. Hiperglisemi ise yaklaşık 4-8. haftalarda gelişmektedir.…”