The endogenous GDF15 is naturally produced by the body under both physiological and pathological conditions and rises significantly in response to metabolic stress, such as intense exercise, fasting, acute HFD or thermoneutral conditions at 30°C [60] and disease states (e.g., cancer [25], obesity and Type 2 diabetes [97]). The gene discussed is GDF15; the disease is obesity due to melanocortin 4 receptor deficiency.