Numerous hormones and cytokines, including glucagon and IL-6, regulate adipose tissue and liver metabolism. These tissues are central controllers of systemic glucose and lipid homeostasis. For instance, the liver has recently been shown to secrete GDF15, a hepatokine that reduces appetite and causes weight loss. The purpose of this thesis was to investigate how glucagon and IL-6 impact adipose tissue and liver metabolism under conditions of thermal and nutritional stress. I also sought to determine mechanisms driving hepatic GDF15 expression and how this effects food intake. In study 1, we show that genetic ablation of the glucagon receptor blunts cold induced browning of white adipose tissue, while glucagon treatment alone is sufficient to induce thermogenic genes in white adipose tissue. In study 2, we found that high saturated fat diet-induced obesity leads to endoplasmic reticulum (ER) stress and hepatic IL-6 resistance, which impairs IL-6’s ability to suppress hepatic glucose output and gluconeogenic genes. In study 3, we demonstrate that activation of the energetic stress sensor, AMPK, is sufficient and necessary for increased expression and secretion of hepatic GDF15 and suppression of food intake. The data presented in this thesis provide new insight into the importance of glucagon and IL-6 in regulating adipose and liver metabolism in situations of thermal stress and over-nutrition. In addition, we provide novel evidence linking AMPK to the induction of GDF15 and the subsequent suppression of food intake.