The hypothalamus is a small structure located in the ventral diencephalon. Hypothalamic neurons sense changes in circulating metabolic cues (e.g. leptin, insulin, glucose), and coordinate responses aimed at maintaining normal body weight and glucose homeostasis. Recent findings indicate that a nicotinamide adenine dinucleotide (NAD(+))-dependent protein deacetylase (namely SIRT1) expressed by hypothalamic neurons is crucial for mounting responses against diet-induced obesity and type 2 diabetes mellitus (T2DM). Here, the repercussions of these findings will be discussed and particular emphasis will be given to the potential exploitation of hypothalamic SIRT1 as a target for the treatment of the rapidly-spreading metabolic disorders of obesity and T2DM. The possible roles of hypothalamic SIRT1 in regulating metabolic ageing processes will also be addressed.