Fructose-induced leptin resistance: discovery of an unsuspected form of the phenomenon and its significance. Focus on "Fructose-induced leptin resistance exacerbates weight gain in response to subsequent high-fat feeding," by Shapiro et al.

THE CONCEPT OF LEPTIN RESISTANCE appeared in the literature almost as soon as the hormone itself was discovered. For purposes of our discussion, leptin resistance will be defined as, “reduced or absent responsiveness to the feeding and body weight inhibitory effects of the hormone in obese individuals in comparison with normal (lean) controls.” Two early reports, demonstrating significant correlations in humans between circulating leptin levels and increasing adiposity, came to the conclusion that resistance to the purported regulatory role of leptin on appetite and body weight must be induced as levels of the hormone increase (18, 43). In short order, the concept of leptin resistance was given experimental support by the finding of decreased ratios of cerebrospinal fluid vs. plasma levels of leptin in obese humans (14, 61). Parallel findings were made at almost the same time in obese rodents (24, 73). Whatever its mechanism, the notion of leptin resistance provided a ready explanation for excess body fat in individuals in the face of extremely high circulating leptin levels. Despite rather compelling initial observations, the notion of leptin resistance remained controversial at early stages of its advancement (4), or was reinterpreted in terms of individual variability in genetically determined leptin response thresholds (56). In fairness, these reviews appeared prior to experimental evidence demonstrating the existence of leptin resistance in obese humans (28, 31, 44). Moreover, findings of significant associations between leptin receptor gene polymorphisms and body mass index, fat mass, and eating behavior in humans were subsequently published (15, 21, 69). Nevertheless, it was not until experimental demonstrations of the phenomenon in outbred animals and subsequent analyses of the biological mechanisms involved that the notion gained widespread acceptance. Experimental leptin resistance was first demonstrated in wild-type mice made obese on a high-fat (HF) diet (13). This was followed by numerous reports of leptin resistance in diet-induced obese rodent models in response to central and/or peripheral administration of leptin (25, 70, 72). More careful behavioral analysis of the sequence of events in the induction of diet-induced leptin resistance revealed what appeared to be a two-step process over successive weeks of HF feeding, with the expression of first peripheral, and then central, leptin resistance (23, 39). Parallel work on potential biological mechanisms underlying leptin resistance revealed the saturation at elevated circulating leptin levels of an active blood-brain barrier (BBB) leptin transport mechanism (7, 12), reduced hypothalamic leptin receptor expression (42, 66), and the inhibition of hypothalamic leptin receptor signal transducer and activator of transcription-3 (STAT-3) second messenger signaling (23) in HF-fed animals. Evidence indicates that these biological events may well parallel the behavioral sequence described above in the induction of leptin resistance (23, 38). Newer observations have confirmed earlier findings of leptin receptor downregulation and reduced leptin binding at hypothalamic sites (32, 40), and additional work has expanded our understanding of the second messenger alterations underlying central leptin resistance. Thus, two intracellular inhibitory factors have been identified (9, 74), suppressor of cytokine signaling-3 and protein tyrosine phosphatase-1B, which reduce leptin receptor signaling by preventing activation of or dephosphorylating the janus-kinase component of the receptor, respectively. These discoveries have permitted a more sophisticated analysis of second messenger mechanisms potentially contributing to central leptin resistance when circulating leptin levels become elevated (29, 52). Leptin resistance is today recognized as a significant contributor to obesity with interest focused on its potential role in the onset vs. maintenance of the obese state (3, 45, 59).