Glucose & energy homeostasis: Lessons from animal studies

Glucose in our body is maintained within a narrow range by the humoral control and a 'lipostat' system regulated by leptin from adipose tissues, which keep our accumulated fat stores in check. Any disturbance in this delicately poised homeostasis could be disastrous as it can lead to obesity and its associated metabolic manifestations. Laboratory animals, especially rodents, have contributed to our knowledge in understanding this physiological mechanism through an array of genetic and non-genetic animals developed over the years. Two rat mutant obese models-Wistar inbred at National Institute of Nutrition (WNIN)/Ob-obese rats with normal glucose levels and WNIN/GR-Ob-obese with impaired glucose tolerance were developed in the National Centre for Laboratory Animal Sciences (Now ICMR-National Animal Resource Facility for Biomedical Research) at Hyderabad, India. These animals are unique, as, unlike the earlier models, they show all types of degenerative disorders associated with obesity, within a single system. Thus they show impairment in all the major organs of the body - liver, pancreas, kidney, bones, muscles, gonads, brain, eyes, and are sensitive to diet manipulations, have compromised immunity, often develop tumours and have reduced life span. One may argue that there are limitations to one's interpretations from animal studies to human application, but then one cannot shut one's eyes to the new lessons they have taught us in modifying our life styles.

Genetic & epigenetic approach to human obesity.

Obesity is an important clinical and public health challenge, epitomized by excess adipose tissue accumulation resulting from an imbalance in energy intake and energy expenditure. It is a forerunner for a variety of other diseases such as type-2-diabetes (T2D), cardiovascular diseases, some types of cancer, stroke, hyperlipidaemia and can be fatal leading to premature death. Obesity is highly heritable and arises from the interplay of multiple genes and environmental factors. Recent advancements in Genome-wide association studies (GWAS) have shown important steps towards identifying genetic risks and identification of genetic markers for lifestyle diseases, especially for a metabolic disorder like obesity. According to the 12th update of Human Obesity Gene Map there are 253 quantity trait loci (QTL) for obesity related phenotypes from 61 genome wide scan studies. Contribution of genetic propensity of individual ethnic and racial variations in obesity is an active area of research. Further, understanding its complexity as to how these variations could influence ones susceptibility to become or remain obese will lead us to a greater understanding of how obesity occurs and hopefully, how to prevent and treat this condition. In this review, various strategies adapted for such an analysis based on the recent advances in genome wide and functional variations in human obesity are discussed.

WNIN/GR-Ob - An insulin-resistant obese rat model from inbred WNIN strain.

Background & objectives: WNIN/GR-Ob is a mutant obese rat strain with impaired glucose tolerance (IGT) developed at the National Institute of Nutrition (NIN), Hyderabad, India, from the existing 80 year old Wistar rat (WNIN) stock colony. The data presented here pertain to its obese nature along with IGT trait as evidenced by physical, physiological and biochemical parameters. The study also explains its existence, in three phenotypes: homozygous lean (+/+), heterozygous carrier (+/-) and homozygous obese (-/-). Methods: Thirty animals (15 males and 15 females) from each phenotype (+/+, +/-, -/-) and 24 lean and obese (6 males and 6 females) rats were taken for growth and food intake studies respectively. Twelve adult rats from each phenotype were taken for body composition measurement by total body electrical conductivity (TOBEC); 12 rats of both genders from each phenotype at different ages were taken for clinical chemistry parameters. Physiological indices of insulin resistance were calculated according to the homeostasis model assessment for insulin resistance (HOMA-IR) and also by studying U14C 2-deoxy glucose uptake (2DG). Results: WNINGR-Ob mutants had high growth, hyperphagia, polydipsia, polyurea, glycosuria, and significantly lower lean body mass, higher fat mass as compared with carrier and lean rats. These mutants, at 50 days of age displayed abnormal response to glucose load (IGT), hyperinsulinaemia, hypertriglyceridaemia, hypercholesterolaemia and hyperleptinaemia. Basal and insulin-stimulated glucose uptakes by diaphragm were significantly decreased in obese rats as compared with lean rats. Interpretation & conclusions: Obese rats of the designated WNIN/GR-Ob strain showed obesity with IGT, as adjudged by physical, physiological and biochemical indices. These indices varied among the three phenotypes, being lowest in lean, highest in obese and intermediate in carrier phenotypes thereby suggesting that obesity is inherited as autosomal incomplete dominant trait in this strain. This mutant obese rat model is easy to propagate, and can easily be transformed to frank diabetes model by dietary manipulation and thus can be used for screening anti-diabetic drugs.

Animal models of obesity & their usefulness in molecular approach to obesity.

Obesity, a multifactorial nutrition disorder, is no longer the problem of the affluent West; it has been slowly gaining entry in to developing countries as well. Ever since the first demonstration of an experimental hypothalamic obese rat model, laboratory animals have been in the forefront of basic research concerned with this important metabolic disease. Apart from nongenetic models, an array of genetic murine models of obesity is now available. Over the years the obese loci in these mutants were localised, and most of them have been cloned. Among them leptin and its receptor--the first gene products to be identified, have revolutionised the field, and the possibility of a 'lipostat' mechanism operating in the body is no longer in the realm of imagination. Studies are now on, to identify the murine obese genes in the human population with a view to understand the problem and intervene therapeutically. We have recently developed a new rat model of obesity in our animal facilities, which has several advantages over the existing Western models. It is hoped, that this new model will strengthen and expand our knowledge on obesity--an interesting but complex syndrome.

In vitro effects of gossypol on testicular lactic dehydrogenase-X and other dehydrogenases.

The in vitro inhibition of several rat testis dehydrogenases by gossypol was examined. Inclusion of the coenzyme (substrate for NADP+-isocitrate dehydrogenase) in the preincubation mixture containing the enzyme and gossypol, protected the enzymes against inhibition by gossypol. Lactic dehydrogenase-X was amongst the least protected enzymes. This, coupled with its low Ki for gossypol makes it one of the most vulnerable target enzymes in vivo for gossypol action. The inhibition kinetics for lactic dehydrogenase-X were competitive when NADH was present during preincubation, but non-competitive when the coenzyme was excluded during preincubation. In the latter condition, the enzyme seems to undergo progressive inactivation with time causing a nonreversible type of inhibition.