Zhang J, Speth RC, Simasko S, Ritter RC (2003) Hypothalamic injection of targeted toxin for cholecystokinin receptive neurons leads to increased 24 hour food intake and weight gain. Neuroscience 2003 Abstracts 830.3. Society for Neuroscience, New Orleans, LA.
Summary: Peptides conjugated to the ribosomal toxin, saporin, bind to their specific G-protein coupled receptors, and are internalized. Once internalized, saporin inactivates ribosomes, selectively killing the receptive cells. We are using cholecystokinin (CCK)-saporin to selectively destroy CCK receptive neurons that may participate in the control of food intake and body weight. We have demonstrated that CCK-saporin binds to CCK-A receptors (Approximate IC50, 3nM), and evokes an increase in cytosolic calcium, which is blocked by the CCK-A receptor antagonist, lorglumide. Thus CCK-saporin has properties that recommend it as a targeted toxin of CCK-receptive neurons. We injected CCK-saporin (138 nM in 500 nl) bilaterally into the medial hypothalamus, an area where CCK-A receptors are expressed. CCK-saporin did not change 24h chow intake or weight gain. However, when rats were fed high fat diet, CCK-saporin treated rats increased their 24h food intake and gained nearly twice the weight as control rats during 14 days on this diet. Following an overnight fast CCK-saporin injected rats ate significantly more high fat diet than controls during the first 30 min after return of food. Nonetheless, both the CCK-saporin injected rats and controls reduced their food intake in response to intraperitoneal CCK-8. Our results suggest that ventromedial hypothalamic CCK receptors participate in control of 24h food intake and body weight gain. Our results also suggest that CCK-saporin may be a valuable tool for investigating the participation of discrete populations of CCK-sensitive neurons in various physiological responses.
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