Obesity is a major public health problem. Excess adiposity reflects an imbalance between food intake and energy expenditure, resulting from complex interactions between genetic and environmental factors. In animals and humans, the control of energy homeostasis is performed by the Central Nervous System (CNS) through neuroendocrine connections, in which circulating peripheral hormones such as leptin and insulin provide a signal to specialized neurons of the hypothalamus reflecting body fat stores, and inducing appropriate responses to maintain the stability of these stores. Obesity is commonly associated with central resistance to both leptin and insulin actions. In experimental animals, high-fat diets can induce an inflammatory process in the hypothalamus, which impairs leptin and insulin intracellular signaling pathways and results in hyperphagia, decreased energy expenditure and ultimately obesity. Recent evidence, obtained from neuroimaging studies and analysis of inflammatory markers in the cerebrospinal fluid of obese subjects, suggest that similar alterations may be also found in humans. In this review, we briefly present the mechanisms involved with deterioration of homeostatic control of energy balance in animal models of obesity and the current evidence of hypothalamic dysfunction in obese humans.