In mammals, changes in the metabolic state, including obesity, fasting, cold challenge, and high-fat diets (HFDs), activate complex immune responses. In many strains of rodents, HFDs induce a rapid systemic inflammatory response and lead to obesity. Little is known about the molecular signals required for HFD-induced phenotypes. We studied the function of the receptor for advanced glycation end products (RAGE) in the development of phenotypes associated with high-fat feeding in mice. RAGE is highly expressed on immune cells, including macrophages. We found that high-fat feeding induced expression of RAGE ligand HMGB1 and carboxymethyllysine-advanced glycation end product epitopes in liver and adipose tissue. Genetic deficiency of RAGE prevented the effects of HFD on energy expenditure, weight gain, adipose tissue inflammation, and insulin resistance. RAGE deficiency had no effect on genetic forms of obesity caused by impaired melanocortin signaling. Hematopoietic deficiency of RAGE or treatment with soluble RAGE partially protected against peripheral HFD-induced inflammation and weight gain. These findings demonstrate that high-fat feeding induces peripheral inflammation and weight gain in a RAGE-dependent manner, providing a foothold in the pathways that regulate diet-induced obesity and offering the potential for therapeutic intervention.

OBJECTIVEPrevious studies showed that genetic deletion or pharmacological blockade of the receptor for advanced glycation end products (RAGE) prevents the early structural changes in the glomerulus associated with diabetic nephropathy. To overcome limitations of mouse models that lack the progressive glomerulosclerosis observed in humans, we studied the contribution of RAGE to diabetic nephropathy in the OVE26 type 1 mouse, a model of progressive glomerulosclerosis and decline of renal function.RESEARCH DESIGN AND METHODSWe bred OVE26 mice with homozygous RAGE knockout (RKO) mice and examined structural changes associated with diabetic nephropathy and used inulin clearance studies and albumin:creatinine measurements to assess renal function. Transcriptional changes in the Tgf-β1 and plasminogen activator inhibitor 1 gene products were measured to investigate mechanisms underlying accumulation of mesangial matrix in OVE26 mice.RESULTSDeletion of RAGE in OVE26 mice reduced nephromegaly, mesangial sclerosis, cast formation, glomerular basement membrane thickening, podocyte effacement, and albuminuria. The significant 29% reduction in glomerular filtration rate observed in OVE26 mice was completely prevented by deletion of RAGE. Increased transcription of the genes for plasminogen activator inhibitor 1, Tgf-β1, Tgf-β–induced, and α1-(IV) collagen observed in OVE26 renal cortex was significantly reduced in OVE26 RKO kidney cortex. ROCK1 activity was significantly lower in OVE26 RKO compared with OVE26 kidney cortex.CONCLUSIONSThese data provide compelling evidence for critical roles for RAGE in the pathogenesis of diabetic nephropathy and suggest that strategies targeting RAGE in long-term diabetes may prevent loss of renal function.

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Peripheral neuropathy and insensate limbs and digits cause significant morbidity in diabetic individuals. Previous studies showed that deletion of the receptor for advanced end-glycation products (RAGE) in mice was protective in long-term diabetic neuropathy. Here, we tested the hypothesis that RAGE suppresses effective axonal regeneration in superimposed acute peripheral nerve injury attributable to tissue-damaging inflammatory responses. We report that deletion of RAGE, particularly in diabetic mice, resulted in significantly higher myelinated fiber densities and conduction velocities consequent to acute sciatic nerve crush compared with wild-type control animals. Consistent with key roles for RAGE-dependent inflammation, reconstitution of diabetic wild-type mice with RAGE-null versus wild-type bone marrow resulted in significantly improved axonal regeneration and restoration of function. Diabetic RAGE-null mice displayed higher numbers of invading macrophages in the nerve segments postcrush compared with wild-type animals, and these macrophages in diabetic RAGE-null mice displayed greater M2 polarization. In vitro, treatment of wild-type bone marrow–derived macrophages with advanced glycation end products (AGEs), which accumulate in diabetic nerve tissue, increased M1 and decreased M2 gene expression in a RAGE-dependent manner. Blockade of RAGE may be beneficial in the acute complications of diabetic neuropathy, at least in part, via upregulation of regeneration signals.

OBJECTIVE-Heightened expression of the receptor for advanced glycation end products (RAGE) contributes to development of systemic diabetic complications, but its contribution to diabetic neuropathy is uncertain. We studied experimental diabetic neuropathy and its relationship with RAGE expression using streptozotocin-induced diabetic mice including a RAGE Ϫ/Ϫ cohort exposed to long-term diabetes compared with littermates without diabetes.RESEARCH DESIGN AND METHODS-Structural indexes of neuropathy were addressed with serial (1, 3, 5, and 9 months of experimental diabetes) electrophysiological and quantitative morphometric analysis of dorsal root ganglia (DRG), peripheral nerve, and epidermal innervation. RAGE protein and mRNA levels in DRG, peripheral nerve, and epidermal terminals were assessed in WT and RAGE Ϫ/Ϫ mice, with and without diabetes. The correlation of RAGE activation with nuclear factor (NF)-B and protein kinase C ␤II (PKC␤II) protein and mRNA expression was also determined. RESULTS-Diabetic peripheral epidermal axons, sural axons,Schwann cells, and sensory neurons within ganglia developed dramatic and cumulative rises in RAGE mRNA and protein along with progressive electrophysiological and structural abnormalities. RAGE Ϫ/Ϫ mice had attenuated structural features of neuropathy after 5 months of diabetes. RAGE-mediated signaling pathway activation for NF-B and PKC␤II pathways was most evident among Schwann cells in the DRG and peripheral nerve.CONCLUSIONS-In a long-term model of experimental diabetes resembling human diabetic peripheral neuropathy, RAGE expression in the peripheral nervous system rises cumulatively and relates to progressive pathological changes. Mice lacking RAGE have attenuated features of neuropathy and limited activation of potentially detrimental signaling pathways. Diabetes