Background: Brown adipose tissue (BAT) is important for cold-and diet-induced thermogenesis. Results: Obesity and chronic exercise antagonistically regulate thermogenic capacity of BAT and subcutaneous white fat (SC WAT). Conclusion: Endurance exercise reduces thermogenic capacity in classical BAT while increasing it in the SC WAT. Significance: Browning of the SC WAT may be potentially used to treat obesity.
The search for putative precursor cells within the pancreas has been the focus of extensive research. Previously, we identified rare pancreas-derived multipotent precursor (PMP) cells in the mouse with the intriguing capacity to generate progeny in the pancreatic and neural lineages. Here, we establish the embryonic pancreas as the developmental source of PMPs through lineage-labeling experiments. We also show that PMPs express insulin and can contribute to multiple pancreatic and neural cell types in vivo. In addition, we have isolated PMPs from adult human islet tissue that are also capable of extensive proliferation, self-renewal, and generation of multiple differentiated pancreatic and neural cell types. Finally, both mouse and human PMP-derived cells ameliorated diabetes in transplanted mice. These findings demonstrate that the adult mammalian pancreas contains a population of insulin(+) multipotent stem cells and suggest that these cells may provide a promising line of investigation toward potential therapeutic benefit.
OBJECTIVE-An important mechanism in the pathogenesis of type 2 diabetes in obese individuals is elevation of plasma free fatty acids (FFAs), which induce insulin resistance and chronically decrease -cell function and mass. Our objective was to investigate the role of oxidative stress in FFA-induced decrease in -cell function. RESEARCH DESIGN AND METHODS-We used an in vivo model of 48-h intravenous oleate infusion in Wistar rats followed by hyperglycemic clamps or islet secretion studies ex vivo and in vitro models of 48-h exposure to oleate in islets and MIN6 cells.RESULTS-Forty-eight-hour infusion of oleate decreased the insulin and C-peptide responses to a hyperglycemic clamp (P Ͻ 0.01), an effect prevented by coinfusion of the antioxidants N-acetylcysteine (NAC) and taurine. Similar to the findings in vivo, 48-h infusion of oleate decreased glucose-stimulated insulin secretion ex vivo (P Ͻ 0.01) and induced oxidative stress (P Ͻ 0.001) in isolated islets, effects prevented by coinfusion of the antioxidants NAC, taurine, or tempol (4-hydroxy-2,2,6,6-tetramethyl-piperidine-1-oxyl). Forty-eight-hour infusion of olive oil induced oxidative stress (P Ͻ 0.001) and decreased the insulin response of isolated islets similar to oleate (P Ͻ 0.01). Islets exposed to oleate or palmitate and MIN6 cells exposed to oleate showed a decreased insulin response to high glucose and increased levels of oxidative stress (both P Ͻ 0.001), effects prevented by taurine. Real-time RT-PCR showed increased mRNA levels of antioxidant genes in MIN6 cells after oleate exposure, an effect partially prevented by taurine. T ype 2 diabetes is characterized by both insulin resistance and defective insulin secretion (1). Obesity is the major predisposing factor for type 2 diabetes and is associated with excessive release of fatty acids from the expanded adipose tissue mass, leading to elevated plasma free fatty acids (FFAs), which are known to induce insulin resistance (2,3). Acute FFA exposure stimulates insulin secretion (4), but studies in vitro and in situ have shown that prolonged FFA exposure decreases glucose-stimulated insulin secretion (GSIS) (5). The effect of prolonged FFA elevation on -cell function in vivo has been more controversial, as absolute GSIS was found to be increased (6 -8), unchanged (9,10), or decreased (11-13) by FFA. However, in most of these studies -cell function was inadequate to compensate for FFA-induced insulin resistance (9 -13), at least in predisposed individuals (14). Although the mechanisms behind FFA-induced decrease in -cell function are unclear, one possibility points toward oxidative stress. Pancreatic -cells have low antioxidant defenses (15) and are thus susceptible to reactive oxygen species (ROS)-induced decrease in function and viability (16,17). Oxidative stress has been implicated in the decrease in GSIS induced by prolonged exposure to glucose (18,19), which is in many respects similar to that induced by prolonged exposure to FFA (4,20). However, whether oxidative stress plays a role in FFA-...
sure to elevated saturated free fatty acid (FFA) levels has been shown to induce endoplasmic reticulum (ER) stress that may contribute to promoting pancreatic -cell apoptosis. Here, we compared the effects of FFAs on apoptosis and ER stress in human islets and two pancreatic -cell lines, rat INS-1 and mouse MIN6 cells. Isolated human islets cultured in vitro underwent apoptosis, and markers of ER stress pathways were elevated by chronic palmitate exposure. Palmitate also induced apoptosis in MIN6 and INS-1 cells, although the former were more resistant to both apoptosis and ER stress. MIN6 cells were found to express significantly higher levels of ER chaperone proteins than INS-1 cells, which likely accounts for the ER stress resistance. We attempted to determine the relative contribution that ER stress plays in palmitate-induced -cell apoptosis. Although overexpressing GRP78 in INS-1 cells partially reduced susceptibility to thapsigargin, this failed to reduce palmitate-induced ER stress or apoptosis. In INS-1 cells, palmitate induced apoptosis at concentrations that did not result in significant ER stress. Finally, MIN6 cells depleted of GRP78 were more susceptible to tunicamycin-induced apoptosis but not to palmitate-induced apoptosis compared with control cells. These results suggest that ER stress is likely not the main mechanism involved in palmitate-induced apoptosis in -cell lines. Human islets and MIN6 cells were found to express high levels of stearoyl-CoA desaturase-1 compared with INS-1 cells, which may account for the decreased susceptibility of these cells to the cytotoxic effects of palmitate. endoplasmic reticulum; lipotoxicity; palmitate LIPOTOXICITY CONTRIBUTES to -cell dysfunction during the development of type 2 diabetes (19,42,48). Chronically elevated levels of free fatty acids (FFAs), particularly saturated FFAs such as palmitate, have been shown to be cytotoxic to pancreatic -cells (8, 10, 24, 30 -33, 41, 46, 50). The monounsaturated FFA oleate on the other hand has been shown to not cause apoptosis of -cells in some studies (16,17,31,32,35), while other studies (11,24,27,33,50) found that it does, particularly those that used the INS-1 -cell line.Palmitate-induced cytotoxicity can result from multiple mechanisms, such as increases in reactive oxygen species (8,18,33), ceramide, and nitric oxide (NO) levels (30, 45) and mitochondrial perturbations (8,18,33). In addition, recent studies (23-25) have shown that endoplasmic reticulum (ER) stress pathways are activated by chronic palmitate exposure.ER stress is caused when the protein folding capacity of the ER is not sufficient to deal with protein folding demands or when an excess of misfolded or aggregated proteins accumulate. Such conditions activate the unfolded protein response (UPR) that attempts to reduce the amount of new protein synthesis, increase folding capacity, and degrade terminally misfolded proteins (20, 53). Prolonged ER stress can lead to apoptosis induction (37, 53) and thus may contribute to palmitate-induced -c...
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.