Effects of tauroursodeoxycholic acid on glucose homeostasis: Potential binding of this bile acid with the insulin receptor.

AIMS: The bile acid (BA), tauroursodeoxycholic acid (TUDCA) regulates glucose homeostasis; however, it is not clear whether its effects on insulin signaling are due to its direct interaction with the insulin receptor (IR) or through activation of the G-coupled BA receptor, TGR5. We, herein, investigated whether the actions of TUDCA on glucose homeostasis occur via IR or TGR5 activation. MAIN METHODS: Glucose homeostasis was evaluated in high-fat diet (HFD)-obese or control (CTL) mice, after 30 days or one intraperitoneal (ip) injection of 300 mg/kg TUDCA, respectively. Molecular docking was performed to investigate the potential binding of TUDCA on the IR and TGR5. KEY FINDINGS: After 30 days of TUDCA treatment, HFD mice exhibited improvements in glucose tolerance and insulin sensitivity, which were abolished when these rodents received the IR antagonist, S961. Molecular docking experiments showed that TUDCA demonstrates high binding affinity for TGR5 and IR and strongly interacts with the insulin binding sites 1 and 2 of the IR. Consistent with this potential agonist activity of TUDCA on IR, CTL mice displayed increased hepatic phosphorylation of AKT after an ip injection of TUDCA. This effect was not associated with altered glycemia in CTL mice and was dependent on IR activation, as S961 prevented hepatic AKT activation by TUDCA. Furthermore, TUDCA activated the hepatic protein kinase A (PKA) and cAMP response element-binding protein (CREB) pathway in CTL mice, even after the administration of S961. SIGNIFICANCE: We provide novel evidence that TUDCA may be an agonist of the IR, in turn activating AKT and contributing, at least in part, to its beneficial effects upon glucose homeostasis.

Fasting and refeeding cycles alter subcutaneous white depot growth dynamics and the morphology of brown adipose tissue in female rats.

Intermittent food restriction (IFR) is used mainly for weight loss; however, its effects on adipose tissue are not known when alternating with an obesogenic diet. To demonstrate its effects on morphological dynamics of fat deposits, female Wistar rats were distributed into groups: standard control (ST-C), with commercial diet; DIO control (DIO-C), with a diet that induces obesity (DIO) during the first and last 15 d, replaced by a standard diet for thirty intermediate days; standard restricted (ST-R), with standard diet during the first and last 15 d, with six cycles of IFR at 50 % of ST-C; and DIO restricted (DIO-R), in DIO during the first and last 15 d, with six cycles of IFR at 50 % of DIO-C. At 105 d of life, white adipose tissue (WAT) and brown adipose tissue (BAT) deposits were collected, weighed and histology performed. The DIO-R group showed higher total food intake (DIO-R 10 768·0 (SEM 357·52) kJ/g v. DIO-C 8868·6 (SEM 249·25) kJ/g, P < 0·0001), energy efficiency during RAI (DIO-R 2·26 (SEM 0·05) g/kJ v. DIO-C 0·70 (SEM 0·03) g/kJ, P < 0·0001) and WAT (DIO-R 5·65 (SEM 0·30) g/100 g v. DIO-C 4·56 (SEM 0·30) g/100 g) than their respective control. Furthermore, IFR groups presented hypertrophy of WAT and BAT, as well as fibrosis in BAT. Thus, IFR can establish prospective resistance to weight loss by favouring changes in adipose tissue morphology, increased energy intake and efficiency. Finally, the DIO diet before and after IFR aggravates the damages caused by the restriction.

D-Pinitol Increases Insulin Secretion and Regulates Hepatic Lipid Metabolism in Msg-Obese Mice.

D-pinitol is one of the major inositol found in plants and studies suggest its potential hypoglycemic and hypolipidemic actions in diabetic rodents. Here, we investigated the actions of D-pinitol on adiposity, and in lipid and glycemic homeostasis in monosodium glutamate (MSG)-obese mice. Swiss mice received daily subcutaneous injections of MSG [(4g/kg of body weight (BW)] or saline [1.25g/kg BW; control (CTL)] during their first five days of life. From 90-120 day-old, half of the MSG and CTL groups received 50 mg D-pinitol/kg BW/day (MPIN and CPIN groups) or vehicle (saline; MSG and CTL groups) by gavage. MSG mice displayed higher abdominal adiposity and hepatic triglycerides (TG) deposition, and increased hepatic expression of lipogenic genes (SREBP-1c, ACC-1 and FASN), but downregulation in AMPKα mRNA. MSG mice also exhibited hyperinsulinemia, islet hypersecretion and hypertrophy, glucose intolerance and insulin resistance. D-pinitol did not change adiposity, glucose intolerance, insulin resistance, but increased hepatic triglycerides (TG) content in MPIN mice, which was associated with increases in gene expressions of SREBP-1c and FASN, but reduction in AMPKα. Furthermore, D-pinitol enhanced insulin secretion in MPIN and CPIN groups. Therefore, D-pinitol enhanced glucose-induced insulin secretion, which may account to enhances hepatic lipogenesis and TG deposition in MPIN mice.

Bisphenol-A exposure worsens hepatic steatosis in ovariectomized mice fed on a high-fat diet: Role of endoplasmic reticulum stress and fibrogenic pathways.

AIMS: Bisphenol (BP)-A exposure can impair glucose and lipid metabolism. However, it is unclear whether this endocrine disruptor (ED) modulates these processes in postmenopause, a period with organic changes that increase the risk for metabolic diseases. Herein, we evaluated the effects of BPA exposure on adiposity, glucose homeostasis and hepatic steatosis in ovariectomized (OVX) mice fed on a high-fat diet (HFD). MAIN METHODS: Adult Swiss female mice were OVX and submitted to a normolipidic diet or HFD and drinking water without [control (OVX CTL) and OVX HFD groups, respectively] or with 1 µg/mL BPA (OVX CBPA and OVX HBPA groups, respectively), for 3 months. KEY FINDINGS: OVX HFD females displayed increased adiposity, glucose intolerance, insulin resistance and moderate hepatic steatosis. This effect was associated with a high hepatic expression of genes involved in lipogenesis (Srebf1 and Scd1), ß-oxidation (Cpt1a) and endoplasmic reticulum (ER) stress (Hspa5 and Hyou1). BPA did not alter adiposity or glucose homeostasis disruptions induced by HFD. However, this ED triggered severe steatosis, exacerbating hepatic fat and collagen depositions in OVX HBPA, in association with a reduction in Mttp mRNA, and up-regulation of genes involved in ß-oxidation (Acox1 and Acadvl), mitochondrial uncoupling (Ucp2), ER stress (Hyou1 and Atf6) and chronic liver injury (Tgfb1and Casp8). Furthermore, BPA caused mild steatosis in OVX CBPA females, increasing the hepatic total lipids and mRNAs for Srebf1, Scd1, Hspa5, Hyou1 and Atf6. SIGNIFICANCE: BPA aggravated hepatic steatosis in OVX mice. Especially when combined with a HFD, BPA caused NAFLD progression, which was partly mediated by chronic ER stress and the TGF-ß1 pathway.

Prolonged bisphenol-A exposure decreases endocrine pancreatic proliferation in response to obesogenic diet in ovariectomized mice.

Research on the deleterious actions of bisphenol (BP)-A have focused on its effects on insulin secretion during pre/perinatal periods or adulthood. Estrogens also modulate endocrine pancreas physiology in females during aging; however, the effects of BPA on islet morphophysiology after menopause have not been investigated. We evaluated the effects of BPA exposure on glucose homeostasis and islet morphofunction in ovariectomized (OVX) mice fed on a high-fat diet (HFD). Adult Swiss female mice were underwent to bilateral ovariectomy, and with the confirmation of the establishment of surgical menopause, the females were then submitted, or not,to a normolipidic diet or HFD [control (CTL) and HFD groups, respectively] without or with 1 µg/mL BPA in their drinking water (CBPA and HBPA groups) for 90 days. HFD females displayed obesity, hyperglycemia, hyperinsulinemia, glucose intolerance and insulin resistance. BPA did not modulate HFD-induced obesity or body glucose impairments in HBPA females, and islets isolated from both the HFD and HBPA groups exhibited insulin hypersecretion. The HBPA islets, however, displayed enlarged islet cells and reduced proliferation, in association with the downregulation of mRNAs encoding PDX-1, NGN3 and CCND2 and upregulation of mRNAs encoding ER-ß, GPR30, TNF-α and IL-1ß in HBPA islets. BPA consumption in OVX mice impaired the islet-cell hyperplasia response to the HFD, partly mediated by increased expression of ER-ß and GPR30, which impaired the expression of major genes involved in islet-cell survival and functionality. Together with higher pro-inflammatory cytokines expression in the islet milieu, these alterations may accelerate ß-cell failure in postmenopause.