Almost 20 years ago, the protein encoded by the ob locus in mice was identified as an adipocyte-secreted hormone, now termed leptin, which functions as a peripheral signal to communicate the organism's energy reserve—and thereby protects against starvation due to insufficient caloric resources. Additional peripheral factors have since been identified that coordinate interorgan crosstalk to manage energy resources. The heart is included in this network through its regulated release of natriuretic peptides A and B—cardiac hormones originally identified as important in blood pressure control. Emerging evidence that natriuretic peptide receptors are expressed in adipose tissue, and that circulating levels of these peptides are decreased in animals and humans with obesity, could imply that natriuretic peptides are also involved in the regulation of energy metabolism. The natriuretic peptides stimulate triglyceride lipolysis in adipocytes, a process also regulated by the sympathetic nervous system. In addition, these two pathways promote uncoupling of mitochondrial respiration and thermogenesis in brown adipocytes. This Review focuses on the roles of the natriuretic peptides and the sympathetic nervous system in regulating adipocyte metabolism. The potential for manipulating the natriuretic peptide pathway to increase energy expenditure in obesity and manage the complications of cardiometabolic disease is also discussed.