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

Abstract

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 (Aβ) production with obesity elevating hypothalamic Bace1 activity and Aβ1–42 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 Aβ1–42 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 Aβ1–42 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.

Efficacy and Safety of Lanabecestat for Treatment of Early and Mild Alzheimer Disease

“…27 Imbalance in Nrg1 function could have resulted in abnormal psychiatric behaviors as previously demonstrated in mouse models. 28 The psychiatric symptoms observed in AMARANTH and DAYBREAK-ALZ may confound the identification of any potential benefit.…”

The beta secretase BACE1 regulates the expression of insulin receptor in the liver

“…Treatment of db/db mice with C3 increases hepatic levels of the mature form of IR, while remaining below (approximately half) of those of the control mice, indicating that BACE1 activity is involved in the reduction of liver IR expression that occurs during diabetes. Pharmacological inhibition of BACE1 is relatively ineffective in db/db mice as denoted by no decrease in IRsol plasma levels, and lack of improvement in glucose homeostasis, suggesting a role for leptin signaling 53 . However, whole-body deletion or inhibition of BACE1 improves the insulin sensitivity of HFD fed mice 28 , 29 .…”

Offspring from maternal nutrient restriction in mice show variations in adult glucose metabolism similar to human fetal growth restriction

“…This marker could also indicate a decreased appetite in MNR offspring, particularly in those with glucose intolerance. Alternatively, leptin resistance occurs in diet-induced obesity, in part, via Aβ 1-42 -induced basal STAT3 phosphorylation in the hypothalamus, 39 indicating that the increased leptin in offspring with impaired glucose homeostasis may be a sign of leptin resistance. Leptin may also play a role in regulation of energy expenditure 39 and behavior changes, such as food preference and total activity, which are also altered in adulthood following IUGR or undernourishment during development.…”

“…Alternatively, leptin resistance occurs in diet-induced obesity, in part, via Aβ 1-42 -induced basal STAT3 phosphorylation in the hypothalamus, 39 indicating that the increased leptin in offspring with impaired glucose homeostasis may be a sign of leptin resistance. Leptin may also play a role in regulation of energy expenditure 39 and behavior changes, such as food preference and total activity, which are also altered in adulthood following IUGR or undernourishment during development. 40,41 Increased serum leptin levels suggest that behaviors and body mass composition may be altered in all or a portion of the MNR offspring and require further investigation.…”