Metabolic phenotype in an AL amyloidosis transgenic mouse model

Abstract

In an attempt to elucidate the in vivo process of protein aggregation and mechanisms of amyloid organ disease, we have engineered a genetically defined mouse model of AL amyloidosis. These transgenic mice broadly expressing a human amyloidogenic lambda 6 immunoglobulin light chain (LC) using a cytomegalovirus (CMV) promoter have circulating LC and develop typical Congo red-positive amyloid deposits in the stomach, previously described at the XIth International Symposium on Amyloidosis in Woods Hole [1]. The CMV-lambda 6 transgenic mice display neurologic and metabolic phenotypes. The transgenic mice are larger and have metabolic dysregulation, accompanied by a decreased respiratory exchange ratio, indicating preferential lipid oxidation. With age, the mice develop hyperglycemia upon glucose challenge. We hypothesize that this may be due to a non-fibril-dependent effect of overexpression of LC in tissues, perhaps pancreas.

Figure 1

Three-month-old transgenic CMV-lambda 6 mice (triangles) have increased body mass compared to non-transgenic controls (circles), (p = 0.0085, t-test with unequal variances). The bar marks the average mass.

Figure 2

RER is decreased in 9-month-old transgenic mice (grey line) when compared to wild-type controls (black lines) during the fed state, indicating a preferential use of fat for energy, rather than glucose.