Cachexia is a wasting syndrome associated with elevated basal energy expenditure and loss of adipose and muscle tissues. It accompanies many chronic diseases including renal failure and cancer and is an important risk factor for mortality. Our recent work demonstrated that tumor-derived PTHrP drives adipose tissue browning and cachexia. Here, we show that PTH is involved in stimulating a thermogenic gene program in 5/6 nephrectomized mice that suffer from cachexia. Fat-specific knockout of PTHR blocked adipose browning and wasting. Surprisingly, loss of PTHR in fat tissue also preserved muscle mass and improved muscle strength. Similarly, PTHR knockout mice were resistant to cachexia driven by tumors. Our results demonstrate that PTHrP and PTH mediate wasting through a common mechanism involving PTHR, and there exists an unexpected crosstalk mechanism between wasting of fat tissue and skeletal muscle. Targeting the PTH/PTHrP pathway may have therapeutic uses in humans with cachexia. Display omitted •5/6 nephrectomy and LLC tumors trigger cachexia and adipose tissue browning•Elevated circulating PTH and PTHrP stimulate browning through their receptor PTHR•PTHR function in fat is required for adipose tissue browning and wasting•Loss of PTHR in fat tissue also attenuates skeletal muscle atrophy Kir et al. reveal a role for the PTH/PTHrP pathway in cachexia driven by kidney failure or cancer and show how PTH and PTHrP stimulate adipose tissue browning through their receptor PTHR. Loss of PTHR in adipocytes blocks atrophy of not only fat tissue, but also skeletal muscle in mice.