Metabolic dysregulation is associated with reproductive disorders but the underlying mechanisms are not clearly understood. Adiponectin is an adipocyte-derived secretory factor that improves insulin sensitivity. Results from animal models indicate that overexpression of adiponectin impairs female fertility. We hypothesized that adiponectin regulates reproduction by altering the hypothalamic-pituitary axis. Mouse LT2 immortalized gonadotrope cells express both adiponectin receptors 1 and 2. Adiponectin increases phosphorylation of AMPK, a downstream target of adiponectin receptors, and reduces basal and GnRH-stimulated LH secretion, acutely. The repression of LH secretion can be mimicked by AICAR, an AMP analog, suggesting the involvement of AMPK. A dominant-negative AMPK mutant or compound C, a selective AMPK inhibitor, potentiates basal LH secretion and abolishes the inhibitory effect of adiponectin. Chronic activation of AMPK by AICAR decreases cellular LH levels and expression of dominant negative AMPK increases cellular LH levels, suggesting a second effect of AMPK to regulate LH synthesis. Lastly, intravenous injection of an adenovirus expressing adiponectin into male mice reduces serum LH levels without changing FSH levels. In conclusion, our results suggest that adiponectin decreases LH secretion in pituitary gonadotropes in an AMPK-dependent manner.