Thyroid transcription factor-1 (TTF-1), a homeodomain-containing transcription factor, is postnatally expressed in discrete areas of the hypothalamus and closely involved in neuroendocrine functions. We previously reported that TTF-1 transcriptionally regulates expression of α-melanocyte-stimulating hormone (α-MSH) and agouti-related peptide (AgRP) in the rat arcuate nucleus and affects feeding behavior via the melanocortin pathway. Moreover, hypothalamic TTF-1 expression was significantly increased in the fasting-induced hypoleptinemia and hypoinsulinemia condition. In this study, we have identified TTF-1 function in the hyperphagia induced by type 1 diabetes. We observed TTF-1 expression in the hypothalamus of streptozotocin (STZ)-induced diabetic rats. TTF-1 expression was significantly increased in the hypothalamus of the diabetic rats that revealed severe weight loss and strong appetite. Surprisingly, the STZ-induced hyperphagia was almost completely disappeared by knocking-down hypothalamic TTF-1 synthesis with intracerebroventricular (icv) administration of an antisense (AS) oligodeoxynucleotide (ODN). Moreover, STZ-induced changes of AgRP and α-MSH expression were completely disappeared by the AS ODN. A higher leptin sensitivity was found in the mice bearing Cre-mediated deletion of TTF-1 gene in the leptin receptor expressing cells (TTF-1 ^LepRCre KO), compared to TTF-1 floxed mice. These results suggest an appetite control action of TTF-1 in the hypothalamus of animals with a low blood concentration of leptin induced by type 1 diabetes.