leptin and 2-mercaptoacetate

A lipoprivic control of feeding has been proposed based on the finding that appetite is stimulated by drugs such as beta-mercaptoacetate (MA) that reduce fatty acid oxidation. The adipose-derived hormone, leptin, has effects on feeding and fat oxidation that are opposite those produced by MA. However, effects of this hormone on MA-induced feeding are not known. Here we examined the effects of endogenous leptin levels and of acute central and peripheral leptin administration on MA-induced feeding. We also examined leptin-induced changes in feeding, body weight, and plasma fuels after capsaicin-induced deletion of the lipoprivic control. MA-induced feeding was not altered under any of these conditions, and leptin's effects were not altered by capsaicin. We then examined MA-induced feeding during chronic leptin treatment. Because chronic leptin produces several distinct metabolic states as body adiposity is reduced, we tested MA before, during, and after leptin treatment at times that coincided with these states. MA-induced feeding was unchanged on d 3 of leptin treatment when rats were in a lipolytic state and rapidly metabolizing body fat stores but reduced on d 10 when they were adipose deplete and their level of fat oxidation was reduced. Together results suggest that the lipoprivic control is normally less active in the fat deplete state than during states associated with fat availability. If so, its insensitivity to leptin would enable the lipoprivic control to operate when dietary fat, adiposity, and leptin levels are elevated. The role played by the lipoprivic control under such conditions remains uncertain.

Topics: Adipose Tissue; Animals; Body Weight; Capsaicin; Dietary Fats; Eating; Fats; Feeding Behavior; Leptin; Lipid Metabolism; Male; Rats; Rats, Sprague-Dawley; Sensory System Agents; Thioglycolates; Triglycerides

Neuropeptide Y (NPY) conjugated to saporin (NPY-SAP), a ribosomal inactivating toxin, is a newly developed compound designed to selectively target and lesion NPY receptor-expressing cells. We injected NPY-SAP into the basomedial hypothalamus (BMH), just dorsal to the arcuate nucleus (ARC), to investigate its neurotoxicity and to determine whether ARC NPY neurons are required for glucoprivic feeding. We found that NPY-SAP profoundly reduced NPY Y1 receptor and alpha MSH immunoreactivity, as well as NPY, Agouti gene-related protein (AGRP), and cocaine and amphetamine-related transcript mRNA expression in the BMH. NPY-SAP lesions were localized to the injection site with no evidence of retrograde transport by hindbrain NPY neurons with BMH terminals. These lesions impaired responses to intracerebroventricular (icv) leptin (5 microg/5 microl x d) and ghrelin (2 microg/5 microl), which are thought to alter feeding primarily by actions on ARC NPY/AGRP and proopiomelanocortin/cocaine and amphetamine-related transcript neurons. However, the hypothesis that NPY/AGRP neurons are required downstream mediators of glucoprivic feeding was not supported. Although NPY/AGRP neurons were destroyed by NPY-SAP, the lesion did not impair either the feeding or the hyperglycemic response to 2-deoxy-D-glucose-induced blockade of glycolysis use. Similarly, responses to glucagon-like peptide-1 (GLP-1, 5 microg/3 microl icv), NPY (5 microg/3 microl icv), cholecystokinin octapeptide (4 microg/kg ip), and beta-mercaptoacetate (68 mg/kg ip) were not altered by the NPY-SAP lesion. Thus, NPY-SAP destroyed NPY receptor-expressing neurons in the ARC and selectively disrupted controls of feeding dependent on those neurons but did not disrupt peptidergic or metabolic controls dependent upon circuitry outside the BMH.

Topics: Agouti-Related Protein; alpha-MSH; Amphetamines; Animals; Arcuate Nucleus of Hypothalamus; Binding, Competitive; Body Weight; Catecholamines; Cholecystokinin; Cocaine; Dopamine Uptake Inhibitors; Ghrelin; Glucagon; Glucagon-Like Peptide 1; Hypothalamus; Immunohistochemistry; In Situ Hybridization; Inhibitory Concentration 50; Intercellular Signaling Peptides and Proteins; Leptin; Ligands; Male; Models, Biological; Neurons; Neuropeptide Y; Peptide Fragments; Peptide Hormones; Peptides; Plant Proteins; Pro-Opiomelanocortin; Protein Binding; Protein Precursors; Proteins; Rats; Rats, Sprague-Dawley; Rhombencephalon; RNA, Messenger; Thioglycolates; Time Factors; Toxins, Biological