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Thiamine supplementation prevents obesity and obesity-associated metabolic disorders in OLETF rats.

ABSTRACT: Thiamine prevents diabetic complications, and its deficiency, resulting from mutation of thiamine transporter gene SLC19A2 has been linked to diabetes mellitus. We previously found that thiamine mitigates metabolic disorders in spontaneous hypertensive rats, harboring defects in glucose and fatty acid metabolism. The current study extends our hypothesis that that thiamine intervention may impact metabolic abnormalities in polyphagia-induced Otsuka Long-Evans Tokushima Fatty (OLETF) rats that lack functional cholecystokinin A receptors. Male OLETF rats exhibit progressive obesity and metabolic disorders similar to human metabolic syndrome. Male OLETF rats (4-week-old) were given free access to water containing either 0.2 % or 0 % of thiamine for 51 weeks. At the end of treatment, blood parameters and cardiac functions were analyzed. After sacrifice, the organs were removed and weights of organs and histological findings were evaluated. In addition, differential gene expression in the liver was analyzed. Thiamine intervention averted obesity, mainly resulting from reduction of visceral adiposity, and prevented metabolic disorders in OLETF rats. Histological evaluation revealed that thiamine alleviated adipocyte hypertrophy, steatosis in the liver, heart, and skeletal muscle, interstitial fibrosis in the heart and kidney, fatty degeneration in the pancreas, thickening of the basement membrane of vasculature, and glomerulopathy and mononuclear cell infiltration in the kidney. Cardiac and renal functions were preserved in thiamine treatment. Seventy-six genes showed at least two-fold difference in hepatic expression with thiamine treatment. Several of them participated in carbohydrate metabolism (Hk1, Pygb, Slc2a8, Rtn4, Rhbdl1, and Tspan8), lipid metabolism (Pla2g15, Por, and Lmf1), vascular physiology (S1pr1, Epha8, Rtn4, Slc7a13, Cdh15, Itga9, Cd151, Cd40lg, Nid1 and Lamb1), and carcinogenesis (Lmo7, Fgfr3, and Dmbt1). Modification of transcript expression well accorded with the findings of blood parameters and organ morphologies. Thiamine prevented polyphagia-induced obesity and metabolic and functional disorders in OLETF rats.

ORGANISM(S): Rattus norvegicus

PROVIDER: GSE19292 | GEO | 2009/12/07

SECONDARY ACCESSION(S): PRJNA120871

REPOSITORIES: GEO

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Project description:Alzheimer's disease (AD) is the most common form of dementia. Obesity in middle age increases AD risk and severity, which is alarming given that obesity prevalence peaks at middle age and obesity rates are accelerating worldwide. Midlife, but not late-life obesity increases AD risk, suggesting that this interaction is specific to preclinical AD. AD pathology begins in middle age, with accumulation of amyloid beta (Aβ), hyperphosphorylated tau, metabolic decline, and neuroinflammation occurring decades before cognitive symptoms appear. We used a transcriptomic discovery approach in young adult (6.5 months old) male and female TgF344-AD rats that overexpress mutant human amyloid precursor protein and presenilin-1 and wild-type (WT) controls to determine whether inducing obesity with a high-fat/high-sugar “Western” diet during preclinical AD increases brain metabolic dysfunction in dorsal hippocampus (dHC), a brain region vulnerable to the effects of obesity and early AD. Analyses of dHC gene expression data showed dysregulated mitochondrial and neurotransmission pathways, and up-regulated genes involved in cholesterol synthesis. Western diet amplified the number of genes that were different between AD and WT rats and added pathways involved in noradrenergic signaling, dysregulated inhibition of cholesterol synthesis, and decreased intracellular lipid transporters. Importantly, the Western diet impaired dHC-dependent spatial working memory in AD but not WT rats, confirming that the dietary intervention accelerated cognitive decline. To examine later consequences of early transcriptional dysregulation, we measured dHC monoamine levels in older (13 months old) AD and WT rats of both sexes after long-term chow or Western diet consumption. Norepinephrine (NE) abundance was significantly decreased in AD rats, NE turnover was increased, and the Western diet attenuated the AD-induced increases in turnover. Collectively, these findings indicate obesity during prodromal AD impairs memory, potentiates AD-induced metabolic decline likely leading to an overproduction of cholesterol, and interferes with compensatory increases in NE transmission.

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Thiamine supplementation prevents obesity and obesity-associated metabolic disorders in OLETF rats.

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