Functional Deficits Precede Structural Lesions in Mice With High-Fat Diet–Induced Diabetic Retinopathy

Abstract

Obesity predisposes to human type 2 diabetes, the most common cause of diabetic retinopathy. To determine if high-fat diet–induced diabetes in mice can model retinal disease, we weaned mice to chow or a high-fat diet and tested the hypothesis that diet-induced metabolic disease promotes retinopathy. Compared with controls, mice fed a diet providing 42% of energy as fat developed obesity-related glucose intolerance by 6 months. There was no evidence of microvascular disease until 12 months, when trypsin digests and dye leakage assays showed high fat–fed mice had greater atrophic capillaries, pericyte ghosts, and permeability than controls. However, electroretinographic dysfunction began at 6 months in high fat–fed mice, manifested by increased latencies and reduced amplitudes of oscillatory potentials compared with controls. These electroretinographic abnormalities were correlated with glucose intolerance. Unexpectedly, retinas from high fat–fed mice manifested striking induction of stress kinase and neural inflammasome activation at 3 months, before the development of systemic glucose intolerance, electroretinographic defects, or microvascular disease. These results suggest that retinal disease in the diabetic milieu may progress through inflammatory and neuroretinal stages long before the development of vascular lesions representing the classic hallmark of diabetic retinopathy, establishing a model for assessing novel interventions to treat eye disease.

Activation of the Stress Response Kinase JNK (c-Jun N-terminal Kinase) Attenuates Insulin Action in Retina through a p70S6K1-dependent Mechanism

“…A link between inflammation and insulin resistance in the retina has been previously proposed (33), yet direct evidence for the molecular mechanism has remained limited. High fat diet-induced retinal inflammation was recently reported in rodent models of type 2 diabetes (22,34). Notably, feeding a high fat diet induces inflammatory markers and JNK phosphorylation in the inner retina before the onset of electroretinogram abnormalities or detectable vascular disease (22), suggesting that JNK activation is an early event in disease progression.…”

“…High fat diet-induced retinal inflammation was recently reported in rodent models of type 2 diabetes (22,34). Notably, feeding a high fat diet induces inflammatory markers and JNK phosphorylation in the inner retina before the onset of electroretinogram abnormalities or detectable vascular disease (22), suggesting that JNK activation is an early event in disease progression. Herein we extend the previous studies by demonstrating that JNK acts to modulate phosphorylation of substrates downstream of S6K1/2 by enhancing the phosphorylation of residues on rictor and IRS1 that are associated with attenuated insulin action.…”

“…Thus, the mechanisms whereby Akt signaling is impaired in type 1 and 2 diabetes are potentially different. However, enhanced JNK activity has been reported both in the retina of rats after streptozotocin administration (36) as wll as in the retina of mice consuming a high fat diet (22).…”

“…Recent studies demonstrate high fat diet-induced retinal degeneration (25) and impaired retinal function (22,26) in rodent models of type 2 diabetes. Moreover, these studies show attenuation of Akt phosphorylation in synaptic layers of the retina concomitant with high fat diet-induced retinal dysfunction (25,26).…”

“…The chronic inflammatory response associated with type 2 diabetes is characterized by abnormal cytokine production and activation of JNK (20,21). Mice consuming a high fat diet exhibit early inflammasome activation within inner retinal layers and induction of JNK (22). Activation of JNK by proinflammatory cytokines inhibits insulin action at least in part by promoting inhibitory serine phosphorylation and degradation of IRS1/2 (23).…”