Obesity, Diabetes and Leptin: Lessons Learned from Obese Hyperglycemic Mice

The recent epidemic nature of obesity and association of obesity with the development of type 2 diabetes demands dissection of the pathophysiology of this morbid disorder which is essential for better understanding of the process of evolution of insulin resistance. Different animal models have been used to explore the mechanism linking obesity to insulin resistance and type 2 diabetes. The discovery of ob gene and its product, leptin, has revealed the signaling system regulating energy balance in rodents. The mice lacking this ob gene, ob/ob mice, display obesity, hyperglycemia and hyperinsulinemia and has been extensively used for the study of type 2 diabetes and for potential drug development. In this review, the features and development of obese hyperglycemic syndrome, the role of leptin in the pathogenesis of the syndrome and finally the applicability of the findings in rodents to body weight regulation and pathogenesis of insulin resistance in humans have been summarized. Ibrahim Med. Coll. J. 2008; 2(2): 72-84 Address for Correspondence: Dr Meftun Ahmed, Associate Professor, Department of Physiology, Ibrahim Medical College, 122 Kazi Nazrul Islam Avenue, Shahbag, Dhaka, Bangladesh, Tel: 8801715425535, Email: [email protected]; [email protected] Introduction In mice a recessive mutant gene, ob, produces obesity leading to hyperinsulinemia and hyperglycemia. Such spontaneous development of obesity and hyperglycemia in mice is generally referred as obese-hyperglycemic syndrome.1 They were first discovered at the Jackson Laboratory, USA in 1949 and found to be homozygous for an autosomal recessive mutation on chromosome 6.2,3 The mutation was propagated in C57BL/6J inbred strain, and also C57BL/KsJ.4,5 Breeding pairs from Jackson Laboratory were obtained by University of Uppsala, Sweden and later by University of Umeå, Sweden (Umeå ob).4,6 These colonies in Sweden are non-inbred colony and the massive islets of Langerhans of the obese mice have been used in studies involving insulin release and islet metabolism.7-9 Continuous research with this ob/ob mice led to the discovery of the ob gene product and indeed opened a new horizon for the diabetes and obesity research. This ob gene product markedly attenuated body weight by reducing food intake and body fat when injected into ob/ob or normal mice10,11 and therefore, was named leptin from the Greek word leptos, meaning thin. The recent official nomenclature for the ob gene in mice is Lep and the ob/ob mice in C57BL/6J background strain is B6.VLepob. In this review the features and development of obese hyperglycemic syndrome and the role of leptin in the pathogenesis of the syndrome as well as the applicability of the findings in rodents to body weight regulation and pathogenesis of insulin resistance in humans has been discussed briefly. Features of obese hyperglycemic syndrome Marked obesity, hypoactivity, hyperphagia, transient hyperglycemia (subsiding around 14-16 weeks), severe hyperinsulinemia and insulin resistance are the cardinal features of obese hyperglycemic syndrome when ob gene is expressed in the C57BL/6J strain background.5,12-14 In contrast to the C57BL/6J strain, BL/Ks ob/ob mice are characterized by obesity, severe hyperglycemia and glucose intolerance, transient hyperinsulinemia, islet atrophy and early death.14,15 Early signs of the obese hyperglycemic syndrome are lower oxygen consumption,16 decreased thermogenesis17 and increased weight gain.12