**8. Leptin resistance with disease**

However, under certain conditions, like obesity, leptin levels decrease in association with leptin resistance. But it is still unclear how the leptin resistance mechanism is exerted throughout the tissue. So far, studies have suggested leptin resistance with metabolic process and revealed a defect in the Ob-R leptin receptor gene [67]. Up to date, the leptin resistance mechanism has been categorized as follows: gene mutation specific to the leptin structure, defect in the transport of leptin through the blood– brain barrier, and malfunctions of leptin receptors. Among these, mutations are rare in humans, occurring in substitution of guanine by adenine at the donor splice site of exon 16 of the leptin gene [68]. Second, the brain's blood vessels usually express leptin receptors and transport leptin into the cerebrospinal fluid. But excessive levels of leptin in the bloodstream decrease the permeability of BBB, thus develops leptin resistance [69]. Finally, the serum level of leptin significantly affects the transcriptional level of the OB (*ob*) gene and the equilibrium of leptin secretion in adipose tissue. In such cases, these dramatic changes promote leptin resistance until leptin level remains standard in the bloodstream. These changes have been widely observed in obesity [70].

Furthermore, several stimuli affect leptin resistance, including the circadian cycle. Interestingly, leptin also develops its leptin resistance, observed in diet-induced obesity [71]. This leptin resistance also provides an environment for the accumulation of immune response against pathogens, particularly high-fat diet-induced inflammation, which activates inflammatory cytokines [72]. But, in-depth leptin resistance mechanisms need much more attention.
