Another anti-feeding frenzy is under way in the industry, followinglast February's flurry of papers and press releases heralding leptin,the putative slimming drug. (See BioWorld Today, Feb. 12 and 20,1996, p. 1.)
At least four leading biotech firms have weighed in since late lastmonth in the obesity-control sweepstakes:
* Amgen Inc., of Thousand Oaks, Calif., said May 20, 1996, that ithas begun Phase I trials at multiple centers in North America "toconfirm the safety and tolerability of recombinant leptin in humans."
* Millennium Pharmaceuticals Inc., of Cambridge, Mass., and F.Hoffmann-La Roche AG, of Basel, Switzerland, researchers reportedin the Proceedings of the National Academy of Sciences (PNAS),dated May 28, 1996, that the "OB protein [i.e. leptin] bindsspecifically to the choroid plexus of mice and rats."
* In that same issue of PNAS, Ligand Pharmaceuticals Inc., of SanDiego, with France's Pasteur Institute, identified the genetic region,or promoter, responsible for controlling leptin expression.
* And today's Nature carries a "News & Views" editorial by ThomasStephens, of the Eli Lilly & Co. Research Laboratories, ofIndianapolis, titled: "Life without neuropeptide Y."
Neuropeptide Y (NPY), Stephens noted, "is the most abundantneuropeptide in the brain, and one of the most important knownplayers in the regulation of body weight." His commentaryaccompanies a paper in Nature by biochemist Richard Palmiter, ofthe Howard Hughes Medical Institute at the University ofWashington, Seattle. Its title: "Sensitivity to leptin and susceptibilityto seizures of mice lacking neuropeptide Y."
NPY, Palmiter wrote, "is thought to function [among its protean rolesin the brain and nervous system] as a central stimulator of feedingbehavior." Turning that "thought" into biological fact, he pointed out,is hampered by the lack of a pharmacological antagonist to the 36-amino-acid NPY transmitter.
To fill this gap, Palmiter and his co-authors genetically engineered atransgenic mouse devoid of the gene that expresses NPY. As of lastMarch, they had over 80 of these NPY-minus mice under study.
These rodents, despite lack of the important brain peptide, hadsurprisingly normal appetites, feeding patterns and body weight.They were fertile and healthy, except for a propensity in some of theanimals to mild seizures _ head and body jerking, tail erection,squeaking _ under certain normally innocuous stresses.
But after food-deprivation for 48 hours, these animals displayedhyperphagia big time _ ferocious appetites and over eating _ andquickly regained the body weight they had lost while fasting.
"These observations," Palmiter suggested, "demonstrate that NPY isnot required for appropriate feeding under basal conditions or afterfood deprivation." Leptin, he observed, supposedly suppressesfeeding and decreases body fat by inhibiting NPY synthesis andrelease from the brain's hypothalamus.
To test the effects of NPY deficiency, the Seattle researchers treatedtheir transgenic mice, and normal controls, to a five-day diet ofrecombinant human or murine leptin. Down came food intake, bodyweight and fat mass in both cohorts.
Conclusion: "Leptin can suppress feeding and promote weight lossvia signaling pathways that are either independent of, or additionalto, NPY."
Obviously, leptin's NPY connection, or lack thereof, still needs work_ and it's getting it.
"NPY-deficient mice," Palmiter concluded, will be useful indetermining the role of NPY in obesity syndromes." Lilly's Stephenscalls them "an important animal model for studying the role of NPYin the long-term regulation of feeding and adiposity."
Among the questions he hopes the model will eventually answer isthis teaser:
"Does the lack of observed abnormality in feeding in [NPY-minus]mice indicate the existence of compensatory mechanisms, or doesNPY play a more complex role in the regulation of feeding than wethink?"
Amgen, in announcing its just-begun leptin trial, made the point that"several years of evaluation in humans will be necessary to fullyevaluate leptin's clinical potential to treat obesity, and to define moreprecisely its biological role in metabolism." It expects this initialstudy of leptin in humans to take "until at least early 1997 tocomplete."
The company acquired, reportedly for $90 million, an exclusivelicense to develop and market products derived from leptin's parentob gene from The Rockefeller University, where it was discovered.(See BioWorld Today, March 1, 1995, p. 1.) n
-- David N. Leff Science Editor
(c) 1997 American Health Consultants. All rights reserved.