The underlying basis for understanding of how brain control energy homeostasis, resides in a functional and coordinate communicating pathways between peripheral endocrine organs and the brain, in which the hypothalamus plays a pivotal role in the integration and processing of peripheral metabolic cues into satiety and feeding signals. Based on human GWAS and targeted mouse mutagenesis models, it has recently been revealed that obesity might due to a brain disease which might be a consequence of a brain misunderstanding the peripheral metabolic status in defense of body weightgain. As matter of fact, a growing body of evidences demonstrate a link between obesity and a defective brain´s nutrient/hormone sensing. Likewise, our studies have shown that hypothalamic astrocytes regulate glucose get access into the brain by sensing peripheral changes in insulin levels and ultimately controlling feeding (García-Cáceres et al., Cell 2016). Using specific transgenic mouse models for targeting metabolic receptors in these glial cells we have demonstrated that not only astrocytes respond to hormones derived from pancreas but also from adipose tissue (leptin), as well as circulating nutrients (lipids, glucose) (Kim et al., Nature Neurosci. 2014; Gao et al., Diabetes 2018; García-Cáceres et al., Cell 2016). Overall our previous work supports that hormone/nutrient signaling in astrocytes is determinant of the manner in which brain sense whole-body metabolic demands. We are now continuing on investigating whether hypothalamic astrocyte-neuron circuits require a precise finely-tuned and coordinated communication with metabolic cues derived from peripheral endocrine organ for maintaining a balanced control of food intake, body weight and metabolism. Furthermore, we hypothesize that impairment of such crosstalk during exposure to hypercaloric environments may contribute to the pathogenesis of obesity and type-2 diabetes. To test this overarching hypothesis, we are developing a functional mouse model for understanding of body-brain connection with particular focus on the role of astrocytes for the control of body weight and energy metabolism in health and disease.