PubMed · 10172764
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M D Brandt. 1996. Practice brief.. https://pubmed.ncbi.nlm.nih.gov/10172764/
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Excessive alcohol consumption is a major health and social issue in our society. Pharmacologic administration of the endocrine hormone fibroblast growth factor 21 (FGF21) suppresses alcohol consumption through actions in the brain in rodents, and genome-wide association studies have identified single nucleotide polymorphisms in genes involved with FGF21 signaling as being associated with increased alcohol consumption in humans. However, the neural circuit(s) through which FGF21 signals to suppress alcohol consumption are unknown, as are its effects on alcohol consumption in higher organisms. Here, we demonstrate that administration of an FGF21 analog to alcohol-preferring non-human primates reduces alcohol intake by 50%. Further, we reveal that FGF21 suppresses alcohol consumption through a projection-specific subpopulation of KLB-expressing neurons in the basolateral amygdala. Our results illustrate how FGF21 suppresses alcohol consumption through a specific population of neurons in the brain and demonstrate its therapeutic potential in non-human primate models of excessive alcohol consumption.
In the accompanying article, we established that in the rat distal colon expression of H, B, and Le(b) blood group antigens by goblet cells is phenotypically fetal in nature. Because of the cocarcinogenic property of ethanol, the present study examined the effects of dietary ethanol consumption, fasting, and withdrawal on the expression of these antigens in the adult rat colon. To that effect, male adult Sprague-Dawley rats were pair-fed ethanol-containing or control Lieber-DeCarli liquid diets for 3 weeks. The effects of ethanol withdrawal were studied in rats fed the ethanol-containing diet for 3 weeks followed by the control diet for 1, 3, and 6 days. In rats fed the control diet, no antigen expression in the distal colon was observed, as expected. Ethanol feeding for 3 weeks resulted in a striking reappearance of H, B, and Le(b) antigens in goblet cells of the distal colon. In colonic crypts, a lower-to-upper crypt gradient of increasing numbers of positive goblet cells was present, suggesting that the induction of antigen expression paralleled the differentiation of goblet cells. After an overnight fast, the number of positive cells was significantly decreased. Withdrawal of ethanol for 1 day further decreased the number of positive goblet cells. The decrease was reflected by a downward shift in the number of positive cells per crypt column, which was more striking in the lower and mid-crypt segments than in the upper segment, suggesting that antigen expression was more labile in immature differentiating goblet cells than in mature ones. No antigen staining of goblet cells was detected after 3 and 6 days of ethanol withdrawal. Hence, expression of H, B, and Le(b) antigens by goblet cells of the distal colon can be modulated by ethanol consumption. Expression in the distal colon of A and Le(a) antigens, which did not exhibit a fetal phenotype, was not affected by ethanol feeding. In conclusion, because of the oncofetal phenotype of H, B, and Le(b) antigens, their reappearance in the distal colon may serve as a cytochemical marker for early recognition of epithelial changes of the colon in ethanol-related cocarcinogenesis before more overt manifestations of neoplasia.
Breast cancer poses a serious public health problem, and it is hoped that identification of genetic and environmental factors that contribute to the development of breast cancer will enhance prevention efforts. Two breast cancer susceptibility genes (BRCA1 and BRCA2) have been identified, and germline mutations in these genes are thought to account for between 5% and 10% of all breast cancer cases. Current findings suggest that mutations in other highly penetrant genes may play an important role in breast cancer susceptibility, and studies aimed at the isolation of these genes are under way. In addition, common variants in a number of gene classes are thought to act as low-penetrance susceptibility alleles, and efforts to identify and characterize these variants are under way. This review discusses the genetic components of susceptibility to breast cancer from the standpoint of both human genetics and rat models.