The expression of leptin, the ob gene product, is increased in adipose tissue in response to feeding and energy repletion, while leptin expression decreases during fasting. Infusion of leptin decreases food intake. Because adipose tissue gene expression is regulated by cytokines induced during infection and because infection is associated with anorexia, we tested whether induction of leptin might occur during the host response to infection. Administration of endotoxin (LPS), a model for gram negative infections, induces profound anorexia and weight loss in hamsters. In fasted animals, LPS increased the expression of leptin mRNA in adipose tissue to levels similar to fed control animals. There is a strong inverse correlation between mRNA levels of leptin and subsequent food intake. TNF and IL-1, mediators of the host response to LPS, also induced anorexia and increased levels of leptin mRNA in adipose tissue. As assessed by immunoprecipitation and Western blotting, circulating leptin protein is regulated by LPS and cytokines in parallel to regulation of adipose tissue leptin mRNA. Induction of leptin during the host response to infection may contribute to the anorexia of infection. (J. Clin. Invest. 1996. 97:2152-2157.)

Leptin's effects are mediated by interactions with a receptor that is alternatively spliced, resulting in at least five different murine forms: Ob-Ra, Ob-Rb, Ob-Rc, Ob-Rd, and Ob-Re. A mutation in one splice form, Ob-Rb, results in obesity in mice. Northern blots, RNase protection assays, and PCR indicate that Ob-Rb is expressed at a relatively high level in hypothalamus and low level in several other tissues. Ob-Ra is expressed ubiquitously, whereas ObRc, -Rd, and -Re RNAs are only detectable using PCR. In hypothalamus, Ob-Rb is present in the arcuate, ventromedial, dorsomedial, and lateral hypothalamic nuclei but is not detectable in other brain regions. These nuclei are known to regulate food intake and body weight. The level of Ob-Rb in hypothalamus is reduced in mice rendered obese by gold thioglucose (GTG), which causes hypothalamic lesions. The obesity in GTG-treated mice is likely to be caused by ablation of Ob-Rb-expressing neurons, which results in leptin resistance.Leptin, a hormone secreted by adipocytes, regulates the size of the adipose tissue mass while affecting satiety and energy metabolism (1-3). Leptin has pleiotypic effects on a number of organ systems and affects reproduction, metabolism, and glucose homeostasis (4-6). Leptin is more potent when given centrally versus peripherally suggesting that some of its effects are mediated via direct actions on receptors in brain (refs. 3 and 7; unpublished data). The leptin receptor, Ob-R, is alternatively spliced, and five different splice forms of the receptor have been identified (8, 9). One form of the receptor, Ob-Rb, is mutant in C57BL͞Ks db͞db mice (9, 10). Both reverse transcription-PCR and RNase protection assays indicate that this splice form is expressed at a relatively high level in hypothalamus, suggesting that leptin interacts with neurons in this brain region (9, 11).The Ob-Rb receptor is different from other forms of the receptor in that it has a long cytoplasmic region with consensus amino acid sequences involved in receptor binding to JAK tyrosine kinases (9). JAK tyrosine kinases are required for signal transduction of receptors in the Ob-R class (12). The cytoplasmic region of Ob-Rb also contains a motif required for binding of the Stat3 transcription factor, a known substrate of JAKs (8, 13). Injections of leptin in vivo result in a dose-dependent activation of Stat3 in hypothalamus within 15 min in wild-type and ob mice but not in db mice (13). The other forms of Ob-R have truncated cytoplasmic regions and presumably cannot by themselves activate JAKs or Stats.In aggregate, these data suggest that leptin's effects are mediated, in part, via binding to the Ob-Rb isoform of the receptor in the hypothalamus. Here we define the tissue distribution of the different Ob-R isoforms in mice and use in situ hybridization to localize the different receptor isoforms in mouse brain and other tissues. We also report the exon and intron boundaries of the different splice forms. Finally, the levels of Ob-Rb are quantitated in mutant mic...

Age-related macular degeneration (AMD), the most common cause of irreversible vision loss in individuals aged older than 50 years, is classified as either wet (neovascular) or dry (nonneovascular). Inherited variation in the complement factor H gene is a major risk factor for drusen in dry AMD. Here we report that a single-nucleotide polymorphism in the promoter region of HTRA1, a serine protease gene on chromosome 10q26, is a major genetic risk factor for wet AMD. A whole-genome association mapping strategy was applied to a Chinese population, yielding a P value of <10(-11). Individuals with the risk-associated genotype were estimated to have a likelihood of developing wet AMD 10 times that of individuals with the wild-type genotype.