4.7 Article

Bace1-dependent amyloid processing regulates hypothalamic leptin sensitivity in obese mice

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SCIENTIFIC REPORTS
卷 8, 期 -, 页码 -

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NATURE PUBLISHING GROUP
DOI: 10.1038/s41598-017-18388-6

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资金

  1. Medical Research Council [MR/K003291/1]
  2. Diabetes UK [12/0004458]
  3. British Heart Foundation [PG/15/44/31574]
  4. Biotechnology and Biological Sciences Research Council CASE award [BB/I015663/1]
  5. Wellcome Trust [WT098012]
  6. AstraZeneca
  7. MRC [MR/K003291/1] Funding Source: UKRI
  8. Alzheimers Research UK [ART-PPG2011A-11] Funding Source: researchfish
  9. Alzheimer's Society [138] Funding Source: researchfish
  10. Biotechnology and Biological Sciences Research Council [1133987] Funding Source: researchfish
  11. British Heart Foundation [PG/15/44/31574] Funding Source: researchfish
  12. Medical Research Council [MR/K003291/1, 1415693, 1545173] Funding Source: researchfish

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Obesity places an enormous medical and economic burden on society. The principal driver appears to be central leptin resistance with hyperleptinemia. Accordingly, a compound that reverses or prevents leptin resistance should promote weight normalisation and improve glucose homeostasis. The protease Bace1 drives beta amyloid (A beta) production with obesity elevating hypothalamic Bace1 activity and A beta 1-42 production. Pharmacological inhibition of Bace1 reduces body weight, improves glucose homeostasis and lowers plasma leptin in diet-induced obese (DIO) mice. These actions are not apparent in ob/ob or db/db mice, indicating the requirement for functional leptin signalling. Decreasing Bace1 activity normalises hypothalamic inflammation, lowers PTP1B and SOCS3 and restores hypothalamic leptin sensitivity and pSTAT3 response in obese mice, but does not affect leptin sensitivity in lean mice. Raising central A beta 1-42 levels in the early stage of DIO increases hypothalamic basal pSTAT3 and reduces the amplitude of the leptin pSTAT3 signal without increased inflammation. Thus, elevated A beta 1-42 promotes hypothalamic leptin resistance, which is associated with diminished whole-body sensitivity to exogenous leptin and exacerbated body weight gain in high fat fed mice. These results indicate that Bace1 inhibitors, currently in clinical trials for Alzheimer's disease, may be useful agents for the treatment of obesity and associated diabetes.

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