Restoration of leptin responsiveness in diet‐induced obese mice using an optimized leptin analog in combination with exendin‐4 or FGF21

Abstract

The identification of leptin as a mediator of body weight regulation provided much initial excitement for the treatment of obesity. Unfortunately, leptin monotherapy is insufficient in reversing obesity in rodents or humans. Recent findings suggest that amylin is able to restore leptin sensitivity and when used in combination with leptin enhances body weight loss in obese rodents and humans. However, as the uniqueness of this combination therapy remains unclear, we assessed whether co-administration of leptin with other weight loss-inducing hormones equally restores leptin responsiveness in diet-induced obese (DIO) mice. Accordingly, we report here the design and characterization of a series of site-specifically enhanced leptin analogs of high potency and sustained action that, when administered in combination with exendin-4 or fibroblast growth factor 21 (FGF21), restores leptin responsiveness in DIO mice after an initial body weight loss of 30%. Using either combination, body weight loss was enhanced compared with either exendin-4 or FGF21 monotherapy, and leptin alone was sufficient to maintain the reduced body weight. In contrast, leptin monotherapy proved ineffective when identical weight loss was induced by caloric restriction alone over a comparable time. Accordingly, we find that a hypothalamic counter-regulatory response to weight loss, assessed using changes in hypothalamic agouti related peptide (AgRP) levels, is triggered by caloric restriction, but blunted by treatment with exendin-4. We conclude that leptin re-sensitization requires pharmacotherapy but does not appear to be restricted to a unique signaling pathway. Our findings provide preclinical evidence that high activity, long-acting leptin analogs are additively efficacious when used in combination with other weight-lowering agents.

20 YEARS OF LEPTIN: Leptin at 20: an overview

“…Studies in animals also showed that pre-treatment of diet-induced obese animals with amylin restored leptin's ability to phosphorylate Stat3 in the hypothalamus, suggesting that this gut peptide might reduce the activity of neural circuits that cause leptin resistance (Turek et al 2010). In animals, leptin's efficacy has also been augmented in combinations with other peptides or hormones raising the possibility that in time it could emerge as part of a combination therapy for obesity (Muller et al 2012). Bariatric surgery is an alternative means for inducing weight loss and, while invasive, can be extremely effective.…”

Functional human antibody CDR fusions as long-acting therapeutic endocrine agonists

“…Compared with hLeptin (t 1/2 = 0.6 h), the hLeptin-Herceptin fusion protein has an extended t 1/2 of 11.8 h (SI Appendix, Table S2). The Fc-hLeptin fusion and PEGylated hLeptin were shown to have half-lives of 10 h in mice and 48 h in rat, respectively (41)(42)(43). Compared with the hGH-CDR3H-coil-Herceptin fusion, hLeptin-CDR3H-coil-Herceptin displays a reduced half-life, which is attributable in part to the different species used in the two PK studies, and may also be due to proteolytic degradation of the fusion protein in vivo (44).…”

Gut hormones such as amylin and GLP-1 in the control of eating and energy expenditure

“…87 Leptin combined with GLP-1 analogs did produce the stronger effects on eating and body weight than single compounds, but the interaction seemed to be (mathematically) additive rather than synergistic. 88 Further, and in contrast to the amylin-induced sensitization of animals to leptin, the effect was only present in animals that had already lost a substantial amount of weight or after animals were switched from an obesogenic high-fat diet to regular rodent chow; 89 hence, manipulations which themselves may affect the leptin sensitivity.…”