Notebook

HARDWIRED HUNGER Two distinct but adjacent sets of cells in the same part of the brain respond in opposite ways to the same hormone: leptin, which, when lacking in the bloodstream, results in a voracious appetite. A group led by Joel K. Elmquist, neuroendocrinology researcher at Beth Israel Deaconess Medical Center and assistant professor of neurology and medicine at Harvard Medical School, set out to understand the leptin pathway by injecting the hormone into rats and following its progress to the lateral hypothalamus area, the part of the brain associated with appetite.In one cell type, leptin bound to neuropeptide Y (NPY), which releases peptides encouraging eating, and in the other cell type it bound to pro-opiomelanocortin (POMC), which releases peptides discouraging eating. Both neuronal cell types expressed SOCS-3, a gene that encodes a protein that acts as a negative feedback regulator of leptin receptor signaling, but only the POMC-expressing cells also expressed Fos, a gene that encodes a transcription factor. FAT AND THE BRAIN: The fat hormone leptin triggers nerve cells in the brain that control eating. In the medial hypothalamus, leptin activates "anoerectic" nerve cells, which release appetite-suppressing neuropeptides (POMC and CART). Simultaneously, leptin inhibits a group of "orexigenic" or appetite-suppressing nerve cells, which release appetite-regulating neuropeptides (NPY and AGRP). The two groups of leptin-sensitive cells send appetite-suppressing signals to key nerve cells in the lateral hypothalamus though to control several behaviors including feeding (ORX and MCH). Considering those markers in combination means that only POMC-expressing cells were directly activated by leptin (C.F. Elias et al., "Leptin differentially regulates NPY and POMC neurons projecting to the lateral hypothalamic area," Neuron, 23:775-86, August 1999). "Moreover, we show that these cells project and innervate cells in the lateral hypothalamus that contain the neuropeptides MCH and orexins (encoded by ORX)." Those neurons control many behaviors, including feeding and sleep. Mice lacking MCH are lean, while ORX knockouts have narcolepsy. "This study links circulating leptin to neurons that control complex behaviors." Leptin may indeed be a more complex hormone than previously thought. Another group, led by Joseph L. Goldstein, a Howard Hughes Medical Institute researcher at the University of Texas Southwestern Medical Center in Dallas, recently demonstrated that the hormone also regulates insulin and glucose uptake--meaning that it could play a role in treating diabetes (I. Shimomura et al., "Leptin reverses insulin resistance and diabetes melitus in mice with congenital lipodystrophy," Nature, 401:73-6, Sept. 2, 1999). --Paul Smaglik KEY DIABETES CLUE Common sense has rewarded the pursuers of an autoantigen that can prompt pathogenic T cells to attack insulin-producing ß cells in mice afflicted with autoimmune or type 1 diabetes. Yale University School of Medicine immunobiology research scientist F. Susan Wong and colleagues have isolated such an antigen just where it might be expected to lie, on an insulin peptide in the pancreas (F.S. Wong et al., "Identification of an MHC class I-restricted autoantigen in type 1 diabetes by screening an organ-specific cDNA library," Nature Medicine, 5:1026-31, September 1999). In 1996, she and colleagues isolated the pathogenic CD8+ clone that recognized the antigen in their latest work, which is the first identification of a CD8+ T cell epitope in the disease. What's more, they located it inside a previously identified epitope for a CD4+ T cell. Both subsets of T lymphocytes are involved in the development of diabetes. "What this says is that this stretch of the protein is very important antigenically, so that's an area to target," Wong notes. She believes it's possible that the newfound autoantigen and the protein glutamic acid decarboxylase (GAD), antigenic to CD4+ T cells, could both be involved in the disease. The infiltrating CD8+ T cells, which their study showed are numerous in young mice, might initially damage ß cells, releasing other, previously hidden antigens to be identified by other autoantibodies. Potential preventive therapy arising from this work would have a modulating effect on the immune system, rather than the metabolic effect that insulin injections now exert. --Steve Bunk VITAMIN E AND PCBs Levels of vitamin E normally found in the body can protect the lining of blood vessels against attack from polychlorinated biphenyls (PCBs), according to a forthcoming study (R.M. Slim et al., "Antioxidant protection against PCB-mediated endothelial cell activation," Toxicological Science, in press) by a team of researchers at the University of Kentucky. The researchers report that in tissue culture, low levels of the vitamin can protect the endothelial cells from oxidative stress induced by PCBs. "Some outreach programs might suggest that people who are at risk take supplements of antioxidants to make them less susceptible to PCB-mediated toxicity," says researcher Bernhard Hennig, professor of nutrition and toxicology. "It's unbelievable how potently vitamin E protects." Most Americans have some PCBs stored in their body, says Larry Robertson, professor of toxicology. "PCBs are constantly moving from blood or fat," he notes. Most of the previous work on the harm of PCB exposure has focused on the liver, notes Robertson. Furthermore, Hennig and his colleagues reported earlier this year that a high-fat diet can increase the endothelial damage caused by PCBs (B. Hennig et al., "Linoleic acid amplifies polychlorinated biphenyl-mediated dysfunction of endothelial cells," Journal of Biochemical and Molecular Toxicology, 13[2]:83-91, 1999). --Harvey Black TIMBERRRRRR! Great oaks grow from tiny acorns because of the walls surrounding plant cells, including the xylem (translation: wood). Cellulose fibrils lend tensile strength to plant cell walls, while an encrusting substance called lignin imparts rigidity. Lignin is great in a 2x4, but it's trouble for the paper industry which uses noxious, expensive chemicals to separate lingnin from cellulose. Now, experiments by Vincent Chiang and colleagues at the Plant Biotechnology Research Center, Michigan Technological University, could make the paper industry "greener." Says Chiang, "After more than a decade's waiting, genetic reduction of lignin in trees is now a reality." A key lignin biosynthetic enzyme, 4CL, activates precursor hydroxycinnamic acids with coenzyme A. Having previously identified two 4CL genes in aspen, one of which is active in stems, the group wondered if they could lower lignin levels using antisense technology. In one recent study, four of 25 aspen lines transgenic for an antisense version of the stem gene showed large reductions in 4CL mRNA at 10 months of age, leading to a more than 90 percent reduction in enzyme levels and up to 45 percent less lignin (W.-J. Hu et al., "Repression of lignin biosynthesis promotes cellulose accumulation and growth in transgenic trees," Nature Biotechnology, 17:808-12, August 1999). The lignin that remained was qualitatively similar to control lignin. Interestingly, the stems had more cellulose and for some reason transgenic plants grew faster. The team will next monitor 600 field-grown trees to see if they retain lignin reduction and observe how the transgenic plants respond to the environment. The technology will have to be transferred to other species, and, compared to crops such as corn, getting mature transgenic trees into production will take time. But that time and effort could pay off, since lignin and its associated biproducts such as dioxin are the sources of water and air pollution. "Wood with genetically reduced lignin would drastically alleviate the environmental issues affiliated with this industry," Chiang concludes. --Barry A. Palevitz NERVE PICTURES Functional magnetic resonance imaging (fMRI) and diffusion imaging alone have led to many advances in neurology, but by themselves, the two techniques have limitations. For example, during fMRI sessions, several areas of the brain often light up simultaneously. "We've always wanted to know how these spots are connected," Thomas E. Conturo, professor of radiology at Washington University School of Medicine in St. Louis, notes. "How are these areas talking to each other to do a certain task?" Combining the two techniques may allow neurologists ways to better map the bundles of nerve fibers that link disparate regions of the brain, Conturo and colleagues report (T.E. Conturo et al., "Tracking neuronal fiber pathways in the living human brain," Proceedings of the National Academy of Sciences, 96:10422-7, Aug. 31, 1999). However, that composite picture wasn't an easy one to develop, he notes. Subjects first underwent normal fMRI while doing a set of tasks. Then, during a separate imaging session, they repeated those tasks, but this time scientists monitored the patient's brain with diffusion imaging--a pixel-by-pixel tracking of water movement along nerve cells. Finally, a nine-member team of physicians, physicists, and computer scientists combined the two images into one. The system has not yet been developed to the point where it could supplant either separate technique. And while the technique does draw pictures of neural highways, it doesn't yet provide millisecond analysis of activity between separate brain regions. "It may not give temporal information, but we can infer some things," Conturo notes. He adds that the technique could aid basic research by helping scientists look for abnormal connections between separate parts of the brain that might be important in diseases such as schizophrenia. --Paul Smaglik TRAUMA AND ALZHEIMER'S Putting pigs through car-crashlike conditions results in pathogenesis resembling Alzheimer's disease--providing physical support for previous epidemiological evidence that brain trauma in humans increases the risk for developing Alzheimer's disease later in life. Douglas H. Smith, associate professor of neurosurgery at the University of Pennsylvania, placed anesthetized pigs in a device that abruptly turned their bodies 100 degrees. That whiplashlike motion--and the sudden interruption to inertia at the end--severed axons connecting neurons scattered throughout the brain. That diffuse axonal injury may lead to Alzheimer's disease, Smith notes. When he and colleagues performed autopsies on the euthanized animals (the crash simulation didn't kill them), they discovered amyloid ß plaques in the brain--the hallmark of Alzheimer's disease (D.H. Smith, "Accumulation of Amyloid ß and tau and the formation of neural filament inclusions following diffuse brain injury in the pig," Journal of Neuropathology and Experimental Neurology, 58:982-92, September 1999). Smith suspects that the plaques result directly from the severed nerve cells. "The parent protein to A ß accumulates in extremely large quantities in axons." Anthony Mamarou, vice chair of neurology and director of research, Medical College of Virginia, applauds the new model and agrees that the study supports epidemiological evidence already implicating brain trauma in Alzheimer's disease pathogenesis. However, he cautions that, because axonal disconnection alone leads to dementia and memory loss, it will be difficult to "tease out" the exact mechanisms responsible for Alzheimer's-like symptoms following trauma. --Paul Smaglik

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