Consumption of a high calorie diet with irregular eating and sedentary behavior habits is typical of the current suboptimal lifestyle, contributing to the development of metabolic diseases such as obesity and type 2 diabetes mellitus. Most notably, the disorder of adipokine secretion in visceral adiposity is a major contributor to metabolic diseases with advancing age. In this regard, spexin and leptin are established as anorexigenic adipokines that can modulate adipogenesis and glucose metabolism by suppressing food intake or increasing energy expenditure, respectively. Emerging evidence points out that spexin levels are lower in the serum and adipose tissue of patients with obesity and/or insulin resistance, whereas circulating levels of leptin are higher in obesity and comorbidities. In turn, spexin and leptin pharmacologically induce beneficial effects on the brain's modulation of food intake and energy expenditure. On the other hand, endocrine crosstalk via spexin and leptin has also been reported in patients suffering from obesity and diabetes. Spexin plays a crucial role in the regulation of leptin secretion and leptin resistance. It should therefore be taken into account that studying the role of spexin in leptin regulation will help us combat the pathologies of obesity caused by leptin resistance.