Differential contribution of dietary fat and monosaccharide to metabolic syndrome in the common marmoset (Callithrix jacchus)

Abstract

There is a critical need for animal models to study aspects type 2 diabetes (T2D) pathogenesis and prevention. While the rhesus macaque is such an established model, the common marmoset has added benefits including reduced zoonotic risks, shorter life span, and a predisposition to birth twins demonstrating chimerism. The marmoset as a model organism for the study of metabolic syndrome has not been fully evaluated. Marmosets fed high-fat or glucose-enriched diets were followed longitudinally to observe effects on morphometric and metabolic measures. Effects on pancreatic histomorphometry and vascular pathology were examined terminally. The glucose-enriched diet group developed an obese phenotype and a prolonged hyperglycemic state evidenced by a rapid and persistent increase in mean glycosylated hemoglobin (HgbA1c) observed as early as week 16. In contrast, marmosets fed a high-fat diet did not maintain an obese phenotype and demonstrated a delayed increase in HgbA1) that did not reach statistical significance until week 40. Consumption of either diet resulted in profound pancreatic islet hyperplasia suggesting a compensation for increased insulin requirements. Although the high-fat diet group developed atherosclerosis of increased severity, the presence of lesions correlated with glucose intolerance only in the glucose-enriched diet group. The altered timing of glucose dysregulation, differential contribution to obesity, and variation in vascular pathology suggests mechanisms of effect specific to dietary nutrient content. Feeding nutritionally modified diets to common marmosets recapitulates aspects of metabolic disease and represents a model that may prove instrumental to elucidating the contribution of nutrient excess to disease development.

Figure 1

Linear correlations between lean mass or fat mass and total body mass in colony housed adult marmosets.

Figure 2

Individual blood glucose responses measured at baseline and following intravenous challenge with 50% dextrose for marmosets fed standard, high-fat, and glucose-enriched diets. Dashed red line represents mean response for each diet group. Solid circles represent animals above the 80^th percentile for area under the curve blood glucose response.

Figure 3

Histologic assessment of common marmoset arterial lesions. Fig 3A: Thoracic aorta from an animal fed a glucose-enriched diet with a type I arterial lesion characterized by localized accumulation of individual and small groups of foam cells. Fig 3B: Thoracic aorta from an animal fed a high-fat diet with a type II arterial lesion, characterized by more extensive infiltration of foam cells expanding the tunica intima and associated with intimal thickening. Fig 3C: Abdominal aorta from the same animal as in Fig 3B showing a type V lesion characterized by minimal extracellular lakes of lipid but severe fibrous thickening causing a narrowing of the arterial lumen. Fig 3D: Iliac artery from an animal fed a high-fat diet with a type VI arterial lesion characterized by fibrous thickening and extracellular lakes of lipid as in the type V lesion, but also accompanied by hemorrhage. This hemorrhage is most likely the result of a fissure in the surface of the arterial lesion which is out of the plane of section.

Figure 4

Histologic and immunohistochemical assessment of common marmoset pancreases. Fig 4A: HE stained slide from a control marmoset fed standard monkey chow showing normal size and distribution of pancreatic islets. Fig 4B: Insulin immunostain of the same section of pancreas showing diffuse positive staining in all islets. Inset shows polarization of insulin staining with most intense staining towards the vascular pole of β cells. Fig 4C: Glucagon immunostain of same section. Inset shows glucagon staining localized mainly to the periphery of islets. In both animals fed a high-fat diet and glucose-enriched diet islets are hyperplastic on HE section (Figs 4D and 4G) and insulin immunostaining is maintained throughout all islets but with reduced intensity (Figs 4E and 4H). Insulin staining maintained polarity within cells (insets of Figs 4E and 4H). Unlike control animals, glucagon staining is consistent throughout the islet rather than focused on the periphery (Figs 4F and 4I).