Skip to main page content
Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
, 105 (20), 7257-62

Leptin Responsiveness Restored by Amylin Agonism in Diet-Induced Obesity: Evidence From Nonclinical and Clinical Studies

Affiliations

Leptin Responsiveness Restored by Amylin Agonism in Diet-Induced Obesity: Evidence From Nonclinical and Clinical Studies

Jonathan D Roth et al. Proc Natl Acad Sci U S A.

Abstract

Body weight is regulated by complex neurohormonal interactions between endocrine signals of long-term adiposity (e.g., leptin, a hypothalamic signal) and short-term satiety (e.g., amylin, a hindbrain signal). We report that concurrent peripheral administration of amylin and leptin elicits synergistic, fat-specific weight loss in leptin-resistant, diet-induced obese rats. Weight loss synergy was specific to amylin treatment, compared with other anorexigenic peptides, and dissociable from amylin's effect on food intake. The addition of leptin after amylin pretreatment elicited further weight loss, compared with either monotherapy condition. In a 24-week randomized, double-blind, clinical proof-of-concept study in overweight/obese subjects, coadministration of recombinant human leptin and the amylin analog pramlintide elicited 12.7% mean weight loss, significantly more than was observed with either treatment alone (P < 0.01). In obese rats, amylin pretreatment partially restored hypothalamic leptin signaling (pSTAT3 immunoreactivity) within the ventromedial, but not the arcuate nucleus and up-regulated basal and leptin-stimulated signaling in the hindbrain area postrema. These findings provide both nonclinical and clinical evidence that amylin agonism restored leptin responsiveness in diet-induced obesity, suggesting that integrated neurohormonal approaches to obesity pharmacotherapy may facilitate greater weight loss by harnessing naturally occurring synergies.

Conflict of interest statement

Conflict of interest statement: The authors declare a conflict of interest (such as defined by PNAS policy). All authors are current or former employees of, and stockholders of, Amylin Pharmaceuticals, Inc. C.M.A. is a former employee of Amylin Pharmaceuticals, Inc., currently employed with Arena Pharmaceuticals, Inc.

Figures

Fig. 1.
Fig. 1.
Synergy of amylin and leptin in DIO-prone rats. (A–F) Cumulative food intake (A, C, and E) and changes in body weight (B, D, and F) after administration in HSD rats (n = 4 per group) (A and B) or in DIO-prone rats (C–F) of leptin (filled inverted triangles), vehicle (open circles), amylin (open triangles), PF(amylin)+leptin (filled circles), or amylin+leptin (filled squares) for 14 d (n = 6 per group) (A–D) or for 12 d (n = 7 per group) (E and F). (G and H) Percentage body fat (G) and lean (H) after 12-d treatment in DIO-prone rats. Mean ± SE: *, P < 0.05 vs. vehicle controls; #, P < 0.05 vs. vehicle controls and monotherapies.
Fig. 2.
Fig. 2.
Translational research findings: Weight loss effect of combined amylin and leptin agonism in DIO rats and overweight/obese humans. (A) Change in body weight for DIO rats pretreated for 14 d with amylin and then maintained on amylin (open triangles) or switched to either leptin monotherapy (filled inverted triangles) or amylin+leptin combination therapy (filled squares) for an additional 28 d. (B) Change in body weight for 93 evaluable human subjects pretreated with pramlintide for 4 weeks and then treated with pramlintide (open triangles), metreleptin (filled inverted triangles), or pramlintide+metreleptin combination (filled squares). Mean ± SE (A) and LS mean ± SE (B): *, P < 0.05 vs. vehicle controls; #, P < 0.01; ##, P < 0.01; ###, P < 0.001 vs. monotherapies.
Fig. 3.
Fig. 3.
Induction of pSTAT3 expression by leptin (15 mg/kg i.p.; white bars) or vehicle (black bars) in arcuate (A), VMH (B), AP (C), and NTS adjacent to AP (rostral) (D) of lean HSD rats or in vehicle-, PF(to amylin)-, or amylin-pretreated (7 d) DIO-prone rats. Mean ± SE: *, P < 0.05 vs. vehicle; #, P < 0.05 vs. PF(amylin).
Fig. 4.
Fig. 4.
Effects of amylin pretreatment on leptin-stimulated pSTAT3. (A–F and I–L) Brightfield images of leptin (15 mg/kg i.p.)-stimulated pSTAT3 immunoreactivity (black dots) in VMH (bregma level −3.4 mm) (A and C–F) and AP (bregma level −13.7 mm) (B and I–L). For orientation, A and B show low-magnification representative images of the entire VMH (A) or AP (B). (G and H) Representative confocal fluorescent images show leptin-stimulated pSTAT3 labeling (green), SF-1 labeling (red), and pSTAT3/SF-1 colocalization (yellow-orange) in the VMH. (Scale bar, 25 μm.) Lean HSD rats (A–C and I) or vehicle-pretreated (D, G, and J), PF-pretreated (E and K), or amylin-pretreated (7 d) (F, H, and L) DIO-prone rats are shown. (Scale bars on brightfield images, 50 μm.)

Similar articles

See all similar articles

Cited by 129 PubMed Central articles

See all "Cited by" articles

LinkOut - more resources

Feedback