Cytosolic malic enzyme 1 (ME1) mediates high fat diet-induced adiposity, endocrine profile, and gastrointestinal tract proliferation-associated biomarkers in male mice.

Obesity and associated hormonal disturbances are risk factors for colon cancer. Cytosolic Malic Enzyme (ME1) generates NADPH used for lipogenesis in gastrointestinal (GI), liver and adipose tissues. We have reported that inclusion of soy protein isolate (SPI) in the diet lowered body fat content and colon tumor incidence of rats fed AIN-93G diet, while others have demonstrated SPI inhibition of rat hepatic ME1 expression. The present study examined the individual and combined effects of dietary SPI and absence of ME1 on: 1) serum concentrations of hormones implicated in colon cancer development, 2) expression of lipogenic and proliferation-associated genes in the mouse colon and small intestine, and 3) liver and adipose expression of lipogenic and adipocytokine genes that may contribute to colon cancer predisposition.Weanling wild type (WT) and ME1 null (MOD-1) male mice were fed high-fat (HF), iso-caloric diets containing either casein (CAS) or SPI as sole protein source for 5 wks. Somatic growth, serum hormone and glucose levels, liver and adipose tissue weights, GI tissue parameters, and gene expression were evaluated.The MOD-1 genotype and SPI-HF diet resulted in decreases in: body and retroperitoneal fat weights, serum insulin, serum leptin, leptin/adiponectin ratio, adipocyte size, colon mTOR and cyclin D1 mRNA abundance, and jejunum FASN mRNA abundance, when compared to WT mice fed CAS-HF. Regardless of diet, MOD-1 mice had reductions in liver weight, liver steatosis, and colon crypt depth, and increases in adipose tissue expression of IRS1 and IRS2, compared to WT mice. SPI-HF diet reduced ME1 gene expression only in retroperitoneal fat.Data suggest that the pharmacological targeting of ME1 or the inclusion of soy protein in the diet may provide avenues to reduce obesity and its associated pro-tumorigenic endocrine environment and improve insulin sensitivity, potentially disrupting the obesity-colon cancer connection

Hepatic lipogenic enzyme gene expression and lipid content.

<p>(A), Relative expression levels of mRNAs encoding ME1 and FASN in the livers of WT and MOD-1 mice of the two diet groups. Data are mean ± SEM of fold change in normalized expression (n = 7 mice/group), relative to WT mice fed CAS-HF diet. (B), Lipid droplet quantity after Oil Red O staining of livers from WT and MOD-1 mice of the two diet groups (n = 3 mice/group). Lowercase letters (a, b) indicate significant differences (P < 0.05). (C), Representative images of liver tissues stained with Oil Red O, scale bar: 100 µm.</p

Malic Enzyme 1 (ME1) Promotes Adiposity and Hepatic Steatosis and Induces Circulating Insulin and Leptin in Obese Female Mice

Malic Enzyme 1 (ME1) supports lipogenesis, cholesterol synthesis, and cellular redox potential by catalyzing the decarboxylation of L-malate to pyruvate, and the concomitant reduction of NADP to NADPH. We examined the contribution of ME1 to the development of obesity by provision of an obesogenic diet to C57BL/6 wild type (WT) and MOD-1 (lack ME1 protein) female mice. Adiposity, serum hormone levels, and adipose, mammary gland, liver, and small intestine gene expression patterns were compared between experimental groups after 10 weeks on a diet. Relative to WT female mice, MOD-1 female mice exhibited lower body weights and less adiposity; decreased concentrations of insulin, leptin, and estrogen; higher concentrations of adiponectin and progesterone; smaller-sized mammary gland adipocytes; and reduced hepatosteatosis. MOD-1 mice had diminished expression of Lep gene in abdominal fat; Lep, Pparg, Klf9, and Acaca genes in mammary glands; Pparg and Cdkn1a genes in liver; and Tlr9 and Ffar3 genes in the small intestine. By contrast, liver expression of Cdkn2a and Lepr genes was augmented in MOD-1, relative to WT mice. Results document an integrative role for ME1 in development of female obesity, suggest novel linkages with specific pathways/genes, and further support the therapeutic targeting of ME1 for obesity, diabetes, and fatty liver disease

Serum hormone concentrations at study termination.

<p>Box plots for: (A), insulin; (B), leptin; and (C), adiponectin concentrations. Boxes indicate the inter-quartile range of 25–75% and median; dots represent individual animals (n = 8–10/group). (D), leptin/adiponectin molar ratio (mean ± SEM). Lowercase letters (a, b, c) indicate significant differences (P < 0.05).</p