In particular, here we pay special attention to novel aspects including: (i) endocannabinoid dynamic changes and levels in the hypothalamus as biomarkers of obesity progression; (ii) recent findings on CB1 in specific cell types, as hypothalamic neurons and astrocytes, or even in intracellular compartments such as membrane associated with mitochondria, and the possible impact on energy balance; and (iii) other new insights going beyond cannabinoids, such as manipulation of proteins involved in endocannabinoids metabolism in the hypothalamus as promising targets against obesity. The gene discussed is CNR1; the disease is obesity due to melanocortin 4 receptor deficiency.