Unraveling the obesity of OLETF rats

Abstract

Cholecystokinin (CCK) is a brain gut peptide that plays an important role in satiety. CCK inhibits food intake by reducing meal size. CCK's satiety actions are mediating through its interaction with CCK1 receptors. Otsuka Long Evans Tokushima Fatty (OLETF) rats are a CCK1 receptor knockout model that allows the study of multiple CCK functions. OLETF rats are hyperphagic with the hyperphagia expressed as a significant increase in the size of meals. OLETF rat obesity is secondary to the hyperphagia and has been propose to derive from two regulatory deficits. One is secondary to the loss of a feedback satiety signal. The other results from increased dorsomedial hypothalamic NPY expression. Recent studies have examined developmental aspects of altered feeding, body weight and orexigenic signaling on OLETF rats. OLETF rats demonstrate increases in meal size in independent ingestion tests as early as two days of age. OLETF pups are also more efficient in suckling situations. Consistent with such developmental differences, examinations of patterns of hypothalamic gene expression in OLETF pups indicate significant increases in DMH NPY expression as early as postnatal Day 15. Access to a running wheel and the resulting exercise have age dependent effects on OLETF food intake and obesity. With running wheel access shortly after weaning, food intake decreases to the levels of LETO controls. When running wheel access is discontinued, food intake temporarily increases resulting in an intermediate phenotype and the absence of diabetes. Together these data demonstrate roles for peripheral CCK and CCK in feeding and body weight control and support the use of the OLETF rat as a model for examining obesity development and for investigating how interventions at critical developmental time points can alter genetic influences on food intake and body weight.

Metabolic effects of activation of CCK receptor signaling pathways by twice-daily administration of the enzyme-resistant CCK-8 analog, (pGlu-Gln)-CCK-8, in normal mice

“…Thus, Otsuka Long Evans Tokushima Fatty (OLEFT) rats, which have a 6847 bp deletion within the gene for the CCK 1 receptor protein resulting in disrupted CCK 1 receptor production, present with hyperglycemia, hyperphagia, impaired glucose tolerance, and mild obesity (Moran 2008). Interestingly, in mice with genetic deletion of the CCK 1 receptor, the adverse effects are much less obvious (Bi et al 2007).…”

“…As such, numerous studies have shown notable therapeutic effectiveness of longer-acting CCK-based compounds (O'Harte et al 1998, Verbaeys et al 2007, 2008, 2009a. In particular, the recently characterized N-terminally modified, enzymatically stable CCK-8 analog, (pGlu-Gln)-CCK-8, causes sustained weight loss and improves both insulin resistance and glucose tolerance in mice with genetically and environmentally induced forms of obesity-diabetes (Irwin et al 2012).…”

Adaptation to lactation in OLETF rats lacking CCK-1 receptors: body weight, fat tissues, leptin and oxytocin

“…We have characterized numerous aspects of their hyperphagia and obesity and many aspects of their development. 24 Although, the absence of CCK-1 receptor signaling is certainly not common in human obesity, there has been a single case report demonstrating obesity in an individual with such a defect, 25 the OLETF rat does share many features found in human obesity. The OLETF rat does not have a primary deficit in leptin signaling.…”

New Insights from Rodent Models of Fatty Liver Disease

“…Unlike the metabolic derangements seen in ob/ob mice, those in OLETF rats are entirely attributable to excess food intake (74). These rats have a defect in the satiety signal mediated by CCK1 as well as the loss of CCK1-mediated inhibition of the orexigenic neuropeptide Y in the brain.…”