Obesity is characterized by markedly decreased ghrelin and growth hormone (GH) secretion. Ghrelin is a GH-stimulating stomach-derived peptide, which also has orexigenic action. Ghrelin supplement may restore decreased GH secretion in obesity, but it may worsen obesity by its orexigenic action. To reveal effects of ghrelin administration on obese animals, we first examined acute GH and orexigenic responses to ghrelin in three different obese and/or diabetic mouse models: db/db mice, mice on a high fat diet (HFD mice), and Akita mice for comparison. GH responses to ghrelin were significantly suppressed in db/db, HFD and Akita mice. Food intake of db/db and Akita mice were basally higher and further stimulation of food intake by ghrelin were suppressed. Pituitary growth hormone secretagogue receptor (GHS-R) mRNA levels in db/db and HFD mice were significantly decreased, which may be partly contribute to decreased GH response to ghrelin in these mice. In Akita mice for comparison, decreased hypothalamic growth hormone releasing hormone (GHRH) mRNA levels may be responsible for decreased GH response, since maximum GH response to ghrelin needs GHRH. When ghrelin were injected to HFD mice with GHRH co-administrated, GH responses to ghrelin were significantly emphasized. HFD mice injected with low dose ghrelin and GHRH for 10 days did not show weight gain. These results indicate that low dose ghrelin and GHRH treatment may restore decreased GH secretion in obesity without worsening obesity.