Alterations in activity and energy expenditure contribute to lean phenotype in Fischer 344 rats lacking the cholecystokinin-1 receptor gene.
ABSTRACT Cholecystokinin (CCK) is hypothesized to inhibit meal size by acting at CCK1 receptors (CCK1R) on vagal afferent neurons that innervate the gastrointestinal tract and project to the hindbrain. Earlier studies have shown that obese Otsuka Long-Evans Tokushima Fatty (OLETF) rats, which carry a spontaneous null mutation of the CCK1R, are hyperphagic and obese. Recent findings show that rats with CCK1R-null gene on a Fischer 344 background (Cck1r(-/-)) are lean and normophagic. In this study, the metabolic phenotype of this rat strain was further characterized. As expected, the CCK1R antagonist, devazepide, failed to stimulate food intake in the Cck1r(-/-) rats. Both Cck1r(+/+) and Cck1r(-/-)rats became diet-induced obese (DIO) when maintained on a high fat diet relative to chow fed controls. Cck1r(-/-) rats consumed larger meals than controls during the dark cycle and smaller meals during the light cycle. These effects were accompanied by increased food intake, total spontaneous activity and energy expenditure during the dark cycle and an apparent reduction in respiratory quotient (RQ) during the light cycle. To assess if enhanced responsiveness to anorexigenic factors may contribute to the lean phenotype we examined the effects of melanotan II (MTII) on food intake and body weight. We found an enhanced effect of MTII in Cck1r(-/-) rats to suppress food intake and body weight following both central and peripheral administration. These results suggest that, despite the increases in meal size and food intake during the dark period, the lean phenotype is potentially driven by increases in total spontaneous activity and energy expenditure.
Full-textDOI: · Available from: Tami Wolden-Hanson, Feb 15, 2014
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ABSTRACT: PURPOSE OF REVIEW: To highlight recent developments relating control of food intake after surgery and the gut-brain axis by reviewing clinically relevant English language articles mainly from January 2011 to March 2013. RECENT FINDINGS: The gut-brain axis involves a number of complex interactions between hypothalamic nuclei and the gastrointestinal tract. In the postoperative period, release of cytokines and neuromodulators are involved in the control of food intake. Analogues of neuromodulators have been developed and tested in animal studies. The emerging field of metabolic surgery has allowed study of these mechanisms in greater detail. SUMMARY: The current epidemic of worldwide obesity demands further research into the mechanisms underlying control of food intake.06/2013; DOI:10.1097/MCO.0b013e3283638e97
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ABSTRACT: Activation of melanocortin 4 receptors (MC4-Rs) in brain nuclei associated with food intake profoundly influences consummatory behavior. Of these nuclei, the dorsal motor vagal nucleus (DMV), which has a dense concentration of MC4-Rs, is an important regulator of gastric tone and motility. Hence, the present study sought to examine the role of MC4-Rs in this nucleus on these activities. Using an in vivo approach, MC4-R agonists, melanotan-II (MT-II) or α-melanocyte stimulating hormone (α-MSH), were unilaterally microinjected into the DMV of rats, and their effects were noted on gastric activity. MT-II decreased phasic contractions, whereas α-MSH increased their amplitude. Both effects were blocked by the MC4-R antagonist SHU9119 or by ipsilateral vagotomy. Microinjection of the agonists (MT-II and α-MSH) into the overlying nucleus of the solitary tract (NTS), an important component of "vago-vagal" gastric circuitry, decreased phasic contractions. In addition, α-MSH reduced gastric tone and mean arterial blood pressure. To study the underlying mechanisms of the effect of MC4-R stimulation on gastric activity, electrophysiological recordings were made from labeled DMV antrum neurons in rat pups and MC4-R(-/-) mice. Bath application of MT-II or α-MSH significantly reduced spontaneous action potentials (but not in MC4-R(-/-) mice). However, in low-calcium ACSF, MT-II decreased neuronal firing, whereas α-MSH increased it. These effects mirror those of our in vivo DMV studies. Altogether, our novel findings show that activation of MC4-Rs in the brainstem, particularly in the medial NTS by the endogenous peptide α-MSH, modulates gastric activity, which may have physiological relevance for food intake and gastric function.The Journal of Neuroscience : The Official Journal of the Society for Neuroscience 08/2013; 33(33):13286-99. DOI:10.1523/JNEUROSCI.0780-13.2013 · 6.75 Impact Factor