BACE2 suppression in mice aggravates the adverse metabolic consequences of an obesogenic diet

Abstract

Objective Pancreatic β-cell dysfunction is a central feature in the pathogenesis of type 2 diabetes (T2D). Accumulating evidence indicates that β-site APP-cleaving enzyme 2 (BACE2) inhibition exerts a beneficial effect on β-cells in different models of T2D. Thus, targeting BACE2 may represent a potential therapeutic strategy for the treatment of this disease. Here, we aimed to investigate the effects of BACE2 suppression on glucose homeostasis in a model of diet-induced obesity. Methods BACE2 knock-out (BKO) and wild-type (WT) mice were fed with a high-fat diet (HFD) for 2 or 16 weeks. Body weight, food intake, respiratory exchange ratio, locomotor activity, and energy expenditure were determined. Glucose homeostasis was evaluated by glucose and insulin tolerance tests. β-cell proliferation was assessed by Ki67-positive nuclei, and β-cell function was determined by measuring glucose-stimulated insulin secretion. Leptin sensitivity was evaluated by quantifying food intake and body weight after an intraperitoneal leptin injection. Neuropeptide gene expression and insulin signaling in the mediobasal hypothalamus were determined by qPCR and Akt phosphorylation, respectively. Results After 16 weeks of HFD feeding, BKO mice exhibited an exacerbated body weight gain and hyperphagia, in comparison to WT littermates. Glucose tolerance was similar in both groups, whereas HFD-induced hyperinsulinemia, insulin resistance, and β-cell expansion were more pronounced in BKO mice. In turn, leptin-induced food intake inhibition and hypothalamic insulin signaling were impaired in BKO mice, regardless of the diet, in accordance with deregulation of the expression of hypothalamic neuropeptide genes. Importantly, BKO mice already showed increased β-cell proliferation and glucose-stimulated insulin secretion with respect to WT littermates after two weeks of HFD feeding, before the onset of obesity. Conclusions Collectively, these results reveal that BACE2 suppression in an obesogenic setting leads to exacerbated body weight gain, hyperinsulinemia, and insulin resistance. Thus, we conclude that inhibition of BACE2 may aggravate the adverse metabolic effects associated with obesity.

BACE1: More than just a β‐secretase

“… 4 , 115 By contrast, BACE2 knockout is associated with an adverse metabolic phenotype, including enhanced weight gain, hyperphagia, hyperinsulinemia, and leptin and insulin resistance. 116 This presents a role for the BACE1 in leptin sensitivity and responsible for energy expenditure and thermogenesis and suggests that the homologous BACE2 enzyme may also play an alternative role.…”

Large yellow tea polysaccharides ameliorate obesity-associated metabolic syndrome by promoting M2 polarization of adipose tissue macrophages

“…tance is primarily attributed to an increase in pancreatic islet β-cell mass and insulin secretion; when β-cells fail to compensate for the insulin resistance, it will ultimately lead to the development of T2D. 27,28 Our results show that LYPs decreased the number and size of pancreatic islets, and reduced the ratio of insulin to glucagon, indicating the preventive effects of LYPs on β cell dysfunction under hyperinsulinemic conditions in HFD-induced obese mice. It is well-established that obesity is primarily caused by the imbalance between energy expenditure and energy intake.…”

Inhibition of Amino Acids Influx into Proximal Tubular Cells Improves Lysosome Function in Diabetes

“…In the model of diet-induced obesity, BACE2 knockout mice leads to exacerbated body weight gain, hyperinsulinemia, and insulin resistance. 29 In addition, BACE2 cleaves the A β protein precursor within the A β domain that accordingly prevents the generation of A β 42 peptides associated with aggregation of the A β , 30 and BACE2 loss-of-function mutation (BACE2 G446R ) showed greater apoptosis and increased levels of A β oligomers in human pluripotent stem cell–derived brain organoids. 31 Further investigation is required to confirm the relevance of BACE2 inhibitor in the treatment of diabetes and obesity.…”