Consumption of a high fat/high sugar (HFHS) diet has not only been identified as risk factor for obesity, but it also predisposes towards type 2 diabetes mellitus (T2DM), by resulting in hyperglycemia and impaired insulin signaling. A targeted metabolic pathway for treatment of T2DM is hepatic gluconeogenesis. Gluconeogenesis is responsible for maintaining blood glucose levels during times of exercise, fasting, and stress. Insulin is responsible for suppressing gluconeogenic activity. However, as the liver becomes insulin resistant, hepatic gluconeogenesis becomes over activated exacerbating T2DM pathology. We aimed to assess whether genistein and/or exercise regulate hepatic gluconeogenesis. C57BL/6J male and female mice aged 5–6 weeks were randomly assigned to one of the following groups (n=8–10/group): lean control (Ln), high fat/high sucrose diet (HFHS), HFHS+Gen (genistein), HFHS+Ex (exercise), and HFHS+Gen+Ex. The HFD consisted of 60% saturated fat, 20% carbohydrate, 20% protein and included sucrose and fructose (42 g/L) in the drinking water. Exercise consisted of daily moderate treadmill running for a total duration of 150 minutes/week for 12 weeks. Genistein dose was 600 mg genistein/kg HF diet. C57BL/6J mice fed HFHS exhibited phenotypes seen in T2DM pathology; including rapid weight gain, hyperinsulinemia and hyperglycemia. Our results demonstrate that serum glucose and insulin levels in males were rescued by Gen+Ex treatment combined compared to controls. Corticosterone levels were significantly elevated in females fed HFHS diet (2755±375 pg/mL, n=6) compared to Ln controls (1449 ± 275 pg/mL, n=7), with significant recovery by Gen+Ex (964±234 pg/mL, n=7). Measures of total protein expression of renal 11βHSD2 (responsible for the conversion of active cortisol to inactive cortisone) however, showed no significant difference indicating that 11βHSD2 may not be playing a role in corticosterone deactivation. We are currently determining total protein expression levels of hepatic 11βHSD1 (responsible for the conversion of corticosterone to its active form). Current studies are also evaluating the roles of two rate limiting enzymes; phosphoenolpyruvate carboxykinase (PEPCK) and glucose‐6‐phosphotase (G6Pase). These studies provide evidence of the protective role that genistein and exercise may provide to ameliorate diabetic‐obesity induced by HFHS diet.Support or Funding InformationSupport: Layla Al‐Nakkash, Tom Broderick were supported by Midwestern‐Arizona Alzheimer's Consortium and Midwestern University Intramural Funds. Chaheyla St Aubin and Amy Fisher were supported by the Department of Biomedical Sciences.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Background: Metabolic syndrome includes a plethora of symptoms ultimately leading to obesity and type 2 diabetes. Obesity has been linked to chronic gastrointestinal dysfunction (constipation, or diarrhea) and specifically females with high BMI have been associated with increased prevalence of diarrhea. We aimed to better understand the influence of high fat-high sugar diet (Western diet) on small intestinal function and to assess sex-dependent effects. Methods: We measured transepithelial short circuit current (Isc) a measure of chloride secretory function, across freshly isolated segments of jejunum from male and female C57Bl/6J mice fed a high fat high sugar diet (HFS) for 12 weeks, compared to lean controls. At the completion of the study, segments of jejunum were frozen for western blot determination of key proteins involved in secretory and absorptive functions and senescence. Intestinal morphology was assessed. Serum cytokine assays were performed. Results: Basal Isc was significantly decreased 70% ( P<0.05) in HFS both females and males versus leans. In females, the HFS-induced decrease in Isc was attributed to a significant loss of CLC2, NKCC1 and CFTR expression whereas in males the decrease in Isc was due to a significant loss of Na/K-ATPase, KCa and NKCC1 expression (indicating interesting sex-dependent etiology). A2BR levels were also dysregulated in HFS fed male and female mice. Inflammatory state and shadowed body weight changes with feeding a western diet. Assessment of intestinal morphology and metabolic profile is being further evaluated. Conclusions: Our data suggests that the reduced basal jejunal Isc in HFS mice is attributed to sex-dependent mechanisms. Improved understanding of Western diet-induced intestinal dysfunctions may provide improved drug targets to treat gastrointestinal disturbances in obesity and diabetes. Midwestern Arizona Alzheimer’s Consortium and Diabetes Action Research and Education Foundation This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Intake of diets high in saturated fat with sugar have been associated with chronic diseases including type 2 diabetes and Alzheimer's disease (AD). This study varied diet and exercise and assessed the changes in adipose metabolism by measuring serum markers, hepatosteatosis, and skeletal muscle lipid metabolism. Male and female 5–6 week old C57BL/6J mice were randomly assigned one of the following groups for 12 weeks (n=8–10/group): lean control (Ln), high fat diet, HFD (60% of calories from fat), and high sucrose/fructose (42 g combined/L drinking water) (HFHS), HFHS with genistein (Gen), HFHS with exercise (Ex), or HFHS with genistein and exercise (Gen‐Ex). Exercise consisted of 150 min/week forced treadmill running. Genistein dose was 600 mg genistein/kg HFD. We hypothesize that Ex and Gen will improve deficits in lipid metabolism associated with diabetes and obesity. Males and females had significant weight increase in HFHS groups compared to Ln groups (40.8% and 27.5% respectively, P<0.05). In males, body weight was significantly lower in Ex (8.9%), Gen (19.2%) and Gen‐Ex mice (32.6%, P<0.05) compared to HFHS controls. In females, body weight was significantly lower in the Gen‐Ex (20.7%, P<0.05) compared to HFHS controls. Weight loss was not attributed to reduced food intake, nor correlated to comparable changes in serum triglyceride. Male liver weight/body weight was increased in HFHS (31.8%, P<0.05) versus Ln, and subsequently reduced by Ex (23.5%), Gen (39%) and Gen‐Ex (52%, P<0.05) compared to HFHS controls. Female liver/body weight was comparable between groups. Glucose tolerance tests (GTT) in subgroups of mice (n=3–5/group) showed rescue of serum glucose in Gen‐Ex males (not females), which reflected concomitant changes in serum insulin. Protein expression of the skeletal muscle lipid metabolism marker, carnitine palmitoyltransferase 1b (CPT1b) was greater (80.5%, n=5/group, P<0.05) in males fed HFHS compared to Ln controls, with no differences in treatment interventions. We aim to provide mechanistic evidence for sex‐dependent effects and to demonstrate an association between genistein‐ and exercise‐mediated improvements in diet induced diabetic‐obesity. Current studies continue to evaluate other metabolic markers. Data currently suggests significant weight changes are not correlated with concomitant changes in skeletal muscle lipid metabolism markers.Support or Funding InformationLayla Al‐Nakkash, and Tom Broderick were supported by Midwestern‐Arizona Alzheimer's Consortium and Midwestern Intramural funds. Amy Fisher and Chaheyla St Aubin were supported by the Department of Biomedical Sciences.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.