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.pramlintide ͉ metreleptin ͉ adiposity ͉ synergy ͉ leptin resistance T he discovery of leptin in 1994 (1) revolutionized our understanding of the biological basis of body-weight regulation and raised hopes that this adipokine could be a breakthrough treatment for obesity. Although leptin plays a pivotal role in regulating energy homeostasis in rodents and humans, its pharmaceutical development as a stand-alone antiobesity agent has proven unsuccessful (2). Although leptin replacement elicits profound weight loss in leptindeficient (Lep ob /Lep ob ) mice and humans (3, 4), even high pharmacological doses elicit only marginal weight loss in non-leptindeficient, diet-induced obese (DIO) rodents and humans (2, 5). The obese state is thus thought to be associated with ''leptin resistance,'' wherein overweight/obese individuals become insensitive to high circulating leptin concentrations (6). The mechanistic basis for leptin resistance is poorly understood, but rodent data implicate leptin transport saturation (7), leptin receptor down-regulation (8), and reduced hypothalamic postreceptor signaling (9, 10).Amylin, a 37-aa peptide hormone cosecreted with insulin from pancreatic ␤-cells (11), binds specific receptors in the hindbrain area postrema (AP) that activate multiple central nervous system (CNS) regions to regulate both glucose and energy homeostasis (12). In obese humans, the amylin analog pramlintide elicited sustained reductions in food intake and body weight (13,14). Amylin-induced weight loss in DIO rats that was observed to be fat-specific with relative...

The neurohormonal control of body weight involves a complex interplay between long‐term adiposity signals (e.g., leptin), and short‐term satiation signals (e.g., amylin). In diet‐induced obese (DIO) rodents, amylin/leptin combination treatment led to marked, synergistic, fat‐specific weight loss. To evaluate the weight‐lowering effect of combined amylin/leptin agonism (with pramlintide/metreleptin) in human obesity, a 24‐week, randomized, double‐blind, active‐drug‐controlled, proof‐of‐concept study was conducted in obese or overweight subjects (N = 177; 63% female; 39 ± 8 years; BMI 32.0 ± 2.1 kg/m2; 93.3 ± 13.2 kg; mean ± s.d.). After a 4‐week lead‐in period with pramlintide (180 µg b.i.d. for 2 weeks, 360 µg b.i.d. thereafter) and diet (40% calorie deficit), subjects achieving 2–8% weight loss were randomized 1:2:2 to 20 weeks of treatment with metreleptin (5 mg b.i.d.), pramlintide (360 µg b.i.d.), or pramlintide/metreleptin (360 µg/5 mg b.i.d.). Combination treatment with pramlintide/metreleptin led to significantly greater weight loss from enrollment to week 20 (−12.7 ± 0.9%; least squares mean ± s.e.) than treatment with pramlintide (−8.4 ± 0.9%; P < 0.001) or metreleptin (−8.2 ± 1.3%; P < 0.01) alone (evaluable, N = 93). The greater reduction in body weight was significant as early as week 4, and weight loss continued throughout the study, without evidence of a plateau. The most common adverse events with pramlintide/metreleptin were injection site events and nausea, which were mostly mild to moderate and decreased over time. These results support further development of pramlintide/metreleptin as a novel, integrated neurohormonal approach to obesity pharmacotherapy.

Previously, we reported that combination treatment with rat amylin (100 microg/kg.d) and murine leptin (500 microg/kg.d) elicited greater inhibition of food intake and greater body weight loss in diet-induced obese rats than predicted by the sum of the monotherapy conditions, a finding consistent with amylin-induced restoration of leptin responsiveness. In the present study, a 3 x 4 factorial design was used to formally test for a synergistic interaction, using lower dose ranges of amylin (0, 10, and 50 microg/kg.d) and leptin (0, 5, 25, and 125 microg/kg.d), on food intake and body weight after 4 wk continuous infusion. Response surface methodology analysis revealed significant synergistic anorexigenic (P < 0.05) and body weight-lowering (P < 0.05) effects of amylin/leptin combination treatment, with up to 15% weight loss at doses considerably lower than previously reported. Pair-feeding (PF) experiments demonstrated that reduction of food intake was the predominant mechanism for amylin/leptin-mediated weight loss. However, fat loss was 2-fold greater in amylin/leptin-treated rats than PF controls. Furthermore, amylin/leptin-mediated weight loss was not accompanied by the counterregulatory decrease in energy expenditure and chronic shift toward carbohydrate (rather than fat) utilization observed with PF. Hepatic gene expression analyses revealed that 28 d treatment with amylin/leptin (but not PF) was associated with reduced expression of genes involved in hepatic lipogenesis (Scd1 and Fasn mRNA) and increased expression of genes involved in lipid utilization (Pck1 mRNA). We conclude that amylin/leptin interact synergistically to reduce body weight and adiposity in diet-induced obese rodents through a number of anorexigenic and metabolic effects.

Four patients with inoperable hepatocellular carcinoma were treated with a magnetic targeted carrier bound to doxorubicin (MTC-DOX) by using a joint magnetic resonance (MR) imaging/conventional angiography system consisting of a 1.5-T short-bore magnet connected to a C-arm angiography unit by a sliding tabletop. Selective transcatheter delivery of the MTC-DOX to the hepatic artery was monitored by using intraprocedural MR imaging, and interim catheter manipulation was performed with fluoroscopic guidance to optimize agent delivery to the tumor and minimize delivery to normal tissue. The final fraction of treated tumor volume ranged from 0.64 to 0.91. The fraction of affected normal liver volume ranged from 0.07 to 0.30. The dual MR imaging/conventional angiography system shows promise for directing magnetically targeted tumor therapies.

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