Green Tea Extract as a Safe and Effective Dietary Supplement: Lessons Learned from Mice

Objectives Green tea extracts (GTEs) are common ingredients among dietary supplements marketed for weight loss and weight management. However, GTEs and their various catechin polyphenols have also been linked to a number of hepatotoxicity cases. Methods The purpose of this study was to investigate, using various mouse models, the hepato- and cardiotoxic potential of a well-characterized GTE; its ability to promote weight loss; and its effect on the gut microbiome. Results Gavaging GTE over a range of 1X–10X mouse equivalent doses (MED) for up to 2 weeks did not elicit significant histomorphological, physiological, biochemical or molecular alterations in the livers of lean B6C3F1 mice. Similarly, no evidence of hepato- or cardiotoxicity was noted when GTE was administered to obese NZO/HlLtJ mice for 8 weeks, either alone or in combination with caffeine (CAF) and/or exercise (EX). Eight weeks of GTE administration in combination with CAF resulted in significant body weight reduction in obese mice, which was further enhanced by EX. Furthermore, GTE/CAF combinations partially mitigated obesity-associated small and large droplet steatosis and decreased both portal and lobular inflammation, demonstrating hepatoprotective capabilities. Administration of GTE at MEDs comparable to those consumed by humans resulted in significant modulation of gut microflora, with increases in beneficial Akkermansia spp. among lean mouse phenotypes being most pronounced. This favorable change in the gut microbiome may provide a mechanistic link to weight loss management. Conclusions Results of this study demonstrate that appropriate doses of caffeinated GTE can serve as a useful adjunct in weight management strategies. Furthermore, clinically relevant doses of GTE/CAF combinations did not produce hepato- or cardiotoxicity, but rather show significant potential to promote liver health by reversing early signs of non-alcoholic fatty liver disease and hepatosteatosis. Funding Sources NIGMS 1P20 GM109005.

Cell specificity of the cytoplasmic Ca2+ response to tolbutamide is impaired in β-cells from hyperglycemic mice

We recently reported that the timing and magnitude of the nutrient-induced Ca2+ response are specific and reproducible for each isolated β-cell. We have now used tolbutamide and arginine to test if the cell specificity exists also for the response to non-nutrient stimulation of β-cells and if so, whether it is disturbed in β-cells from hyperglycemic ob/ob and db/db mice. Zn2+ outflow measurements were used to study the correlation between Ca2+ response and insulin secretion in individual β-cells. Tolbutamide and arginine induced cell-specific Ca2+ responses in lean mouse β-cells both with regard to lag times for [Ca2+]i rise and peak [Ca2+]i heights. β-Cells within intact islets also showed cell-specific timing of their Ca2+ responses to tolbutamide. However, in tolbutamide- and arginine-stimulated single β-cells from ob/ob and db/db mice only the magnitude of Ca2+ response was cell-specific, not the timing. The lag time of tolbutamide-induced insulin secretion was cell-specific in lean mouse β-cells but not in ob/ob mouse cells. Therefore, cell specificity seems to be a robust mechanism, and probably important for an adequate β-cell function. The loss of temporal cell specificity for the response to tolbutamide in single β-cells from hyperglycemic mice may be a sign of KATP- or voltage-dependent calcium channel dysfunction.

Insulin secretion from ob/ob mouse pancreatic islets: effects of neurotransmitters

Effects of glucose, acetylcholine, and norepinephrine on insulin secretion from pancreatic islets of 8- to 9-wk-old female genetically obese (ob/ob) and lean mice were determined. The ob/ob islets were 60% larger in diameter than lean mouse islets, secreted fourfold more insulin in response to glucose, and secreted insulin at lower glucose concentrations than lean islets. In the presence of 15 mM glucose, ob/ob islets showed an 8-fold greater absolute increase in insulin secretion in response to acetylcholine and a 12-fold greater absolute decrease in insulin secretion in response to norepinephrine inhibition compared with lean islets. In the presence of 5 mM glucose, acetylcholine increased insulin secretion by threefold from ob/ob islets with no effect on lean islets. When both ob/ob and lean islets were stimulated by glucose to equivalent levels of insulin secretion, acetylcholine potentiated glucose-induced insulin secretion equally in ob/ob and lean islets. Enhanced glucose-induced responsiveness of ob/ob islets thus can explain the greater acetylcholine potentiation of insulin secretion and probably the greater norepinephrine inhibition of insulin secretion in ob/ob islets compared with lean islets. These data are consistent with the hypotheses that the major alteration in ob/ob mouse islets is in glucose sensitivity and responsiveness, which subsequently increases ob/ob islet susceptibility to neural regulation of insulin secretion.