Obesity results from a caloric imbalance between energy intake, absorption and expenditure. In both rodents and humans, diet-induced thermogenesis contributes to energy expenditure and involves the ...activation of brown adipose tissue (BAT). We hypothesize that environmental toxicants commonly used as food additives or pesticides might reduce BAT thermogenesis through suppression of uncoupling protein 1 (UCP1) and this may contribute to the development of obesity. Using a step-wise screening approach, we discover that the organophosphate insecticide chlorpyrifos suppresses UCP1 and mitochondrial respiration in BAT at concentrations as low as 1 pM. In mice housed at thermoneutrality and fed a high-fat diet, chlorpyrifos impairs BAT mitochondrial function and diet-induced thermogenesis, promoting greater obesity, non-alcoholic fatty liver disease (NAFLD) and insulin resistance. This is associated with reductions in cAMP; activation of p38MAPK and AMPK; protein kinases critical for maintaining UCP1 and mitophagy, respectively in BAT. These data indicate that the commonly used pesticide chlorpyrifos, suppresses diet-induced thermogenesis and the activation of BAT, suggesting its use may contribute to the obesity epidemic.
Nonalcoholic fatty liver disease (NAFLD) is a growing worldwide epidemic and an important risk factor for the development of insulin resistance, type 2 diabetes, nonalcoholic steatohepatitis (NASH), ...and hepatic cellular carcinoma (HCC). Despite the prevalence of NAFLD, lifestyle interventions involving exercise and weight loss are the only accepted treatments for this disease. Over the last decade, numerous experimental compounds have been shown to improve NAFLD in preclinical animal models, and many of these therapeutics have been shown to increase the activity of the cellular energy sensor AMP-activated protein kinase (AMPK). Because AMPK activity is reduced by inflammation, obesity, and diabetes, increasing AMPK activity has been viewed as a viable therapeutic strategy to improve NAFLD. In this review, we propose three primary mechanisms by which AMPK activation may improve NAFLD. In addition, we examine the mechanisms by which AMPK is activated. Finally, we identify 27 studies that have used AMPK activators to reduce NAFLD. Future considerations for studies examining the relationship between AMPK and NAFLD are highlighted.
The AMP-activated protein kinase (AMPK) activates autophagy, but its role in aging and fasting-induced muscle function has not been defined. Here we report that fasting mice lacking skeletal muscle ...AMPK (AMPK-MKO) results in hypoglycemia and hyperketosis. This is not due to defective fatty acid oxidation, but instead is related to a block in muscle proteolysis that leads to reduced circulating levels of alanine, an essential amino acid required for gluconeogenesis. Markers of muscle autophagy including phosphorylation of Ulk1 Ser555 and Ser757 and aggregation of RFP-LC3 puncta are impaired. Consistent with impaired autophagy, aged AMPK-MKO mice possess a significant myopathy characterized by reduced muscle function, mitochondrial disease, and accumulation of the autophagy/mitophagy proteins p62 and Parkin. These findings establish an essential requirement for skeletal muscle AMPK-mediated autophagy in preserving blood glucose levels during prolonged fasting as well as maintaining muscle integrity and mitochondrial function during aging.
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•Muscle AMPK is required for the induction of autophagy during fasting•AMPK is required for proteolysis to maintain blood glucose during fasting•A loss of AMPK accelerates aging-induced myopathy and mitochondrial dysfunction
Bujak et al. highlight a critical role for the energy sensor AMPK in maintaining glycemia and muscle homeostasis. During fasting, muscle AMPK induces autophagy and muscle protein breakdown to prevent hypoglycemia. With old age, AMPK delays the onset of muscle myopathy and mitochondrial dysfunction.
Can feedback solve the too-big-to-fail problem? Garrison-Kimmel, Shea; Rocha, Miguel; Boylan-Kolchin, Michael ...
Monthly notices of the Royal Astronomical Society,
08/2013, Letnik:
433, Številka:
4
Journal Article
Recenzirano
Odprti dostop
The observed central densities of Milky Way dwarf spheroidal galaxies (dSphs) are significantly lower than the densities of the largest (V
max ∼ 35 km s−1) subhaloes found in dissipationless ...simulations of Galaxy-size dark matter hosts. One possible explanation is that gas removal from feedback can lower core densities enough to match observations. We model the dynamical effects of supernova feedback through the use of a time-varying central potential in high-resolution, idealized numerical simulations and explore the resulting impact on the mass distributions of dwarf dark matter haloes. We find that in order to match the observed central masses of M
∼ 106 M dSphs, the energy equivalent of more than 40 000 supernovae must be delivered with 100 per cent efficiency directly to the dark matter. This energy requirement exceeds the number of supernovae that have ever exploded in most dSphs for typical initial mass functions. We also find that, per unit energy delivered and per cumulative mass removed from the galaxy, single blowout events are more effective than repeated small bursts in reducing central dark matter densities. We conclude that it is unlikely that supernova feedback alone can solve the 'too-big-to-fail' problem for Milky Way subhaloes.
We aimed to determine the combined effects of overexpressing plasma membrane fatty acid binding protein (FABPpm) and fatty acid translocase (CD36) on skeletal muscle fatty acid transport to establish ...if these transport proteins function collaboratively. Electrotransfection with either FABPpm or CD36 increased their protein content at the plasma membrane (+75% and +64%), increased fatty acid transport rates by +24% for FABPpm and +62% for CD36, resulting in a calculated transport efficiency of ∼0.019 and ∼0.053 per unit protein change for FABPpm and CD36, respectively. We subsequently used these data to determine if increasing both proteins additively or synergistically increased fatty acid transport. Cotransfection of FABPpm and CD36 simultaneously increased protein content in whole muscle (FABPpm, +46%; CD36, +45%) and at the sarcolemma (FABPpm, +41%; CD36, +42%), as well as fatty acid transport rates (+50%). Since the relative effects of changing FABPpm and CD36 content had been independently determined, we were able to a predict a change in fatty acid transport based on the overexpression of plasmalemmal transporters in the cotransfection experiments. This prediction yielded an increase in fatty acid transport of +0.984 and +1.722 pmol/mg prot/15 s for FABPpm and CD36, respectively, for a total increase of +2.96 pmol/mg prot/15 s. This calculated determination was remarkably consistent with the measured change in transport, namely +2.89 pmol/mg prot/15 s. Altogether, these data indicate that increasing CD36 and FABPpm alters fatty acid transport rates additively, but not synergistically, suggesting an independent mechanism of action within muscle for each transporter. This conclusion was further supported by the observation that plasmalemmal CD36 and FABPpm did not coimmunoprecipitate.
Caloric restriction that promotes weight loss is an effective strategy for treating non-alcoholic fatty liver disease and improving insulin sensitivity in people with type 2 diabetes
. Despite its ...effectiveness, in most individuals, weight loss is usually not maintained partly due to physiological adaptations that suppress energy expenditure, a process known as adaptive thermogenesis, the mechanistic underpinnings of which are unclear
. Treatment of rodents fed a high-fat diet with recombinant growth differentiating factor 15 (GDF15) reduces obesity and improves glycaemic control through glial-cell-derived neurotrophic factor family receptor α-like (GFRAL)-dependent suppression of food intake
. Here we find that, in addition to suppressing appetite, GDF15 counteracts compensatory reductions in energy expenditure, eliciting greater weight loss and reductions in non-alcoholic fatty liver disease (NAFLD) compared to caloric restriction alone. This effect of GDF15 to maintain energy expenditure during calorie restriction requires a GFRAL-β-adrenergic-dependent signalling axis that increases fatty acid oxidation and calcium futile cycling in the skeletal muscle of mice. These data indicate that therapeutic targeting of the GDF15-GFRAL pathway may be useful for maintaining energy expenditure in skeletal muscle during caloric restriction.
Statins reduce lipid levels and are widely prescribed. Statins have been associated with an increased incidence of type 2 diabetes, but the mechanisms are unclear. Activation of the NOD-like receptor ...family, pyrin domain containing 3 (NLRP3)/caspase-1 inflammasome, promotes insulin resistance, a precursor of type 2 diabetes. We showed that four different statins increased interleukin-1β (IL-1β) secretion from macrophages, which is characteristic of NLRP3 inflammasome activation. This effect was dose dependent, absent in NLRP3(-/-) mice, and prevented by caspase-1 inhibition or the diabetes drug glyburide. Long-term fluvastatin treatment of obese mice impaired insulin-stimulated glucose uptake in adipose tissue. Fluvastatin-induced activation of the NLRP3/caspase-1 pathway was required for the development of insulin resistance in adipose tissue explants, an effect also prevented by glyburide. Fluvastatin impaired insulin signaling in lipopolysaccharide-primed 3T3-L1 adipocytes, an effect associated with increased caspase-1 activity, but not IL-1β secretion. Our results define an NLRP3/caspase-1-mediated mechanism of statin-induced insulin resistance in adipose tissue and adipocytes, which may be a contributing factor to statin-induced development of type 2 diabetes. These results warrant scrutiny of insulin sensitivity during statin use and suggest that combination therapies with glyburide, or other inhibitors of the NLRP3 inflammasome, may be effective in preventing the adverse effects of statins.
Sodium-glucose cotransporter 2 inhibitors such as canagliflozin lower blood glucose and reduce cardiovascular events in people with type 2 diabetes through mechanisms that are not fully understood. ...Canagliflozin has been shown to increase the activity of the AMP-activated protein kinase (AMPK), a metabolic energy sensor important for increasing fatty acid oxidation and energy expenditure and suppressing lipogenesis and inflammation, but whether AMPK activation is important for mediating some of the beneficial metabolic effects of canagliflozin has not been determined. We, therefore, evaluated the effects of canagliflozin in female ApoE-/- and ApoE-/-AMPK β1-/- mice fed a western diet. Canagliflozin increased fatty acid oxidation and energy expenditure and lowered adiposity, blood glucose and the respiratory exchange ratio independently of AMPK β1. Canagliflozin also suppressed liver lipid synthesis and the expression of ATP-citrate lyase, acetyl-CoA carboxylase and sterol response element-binding protein 1c independently of AMPK β1. Canagliflozin lowered circulating IL-1β and studies in bone marrow-derived macrophages indicated that in contrast with the metabolic adaptations, this effect required AMPK β1. Canagliflozin had no effect on the size of atherosclerotic plaques in either ApoE-/- and ApoE-/-AMPK β1-/- mice. Future studies investigating whether reductions in liver lipid synthesis and macrophage IL-1β are important for the cardioprotective effects of canagliflozin warrant further investigation.
Aims/hypothesis
Obesity is characterised by lipid accumulation in skeletal muscle, which increases the risk of developing insulin resistance and type 2 diabetes. AMP-activated protein kinase (AMPK) ...is a sensor of cellular energy status and is activated in skeletal muscle by exercise, hormones (leptin, adiponectin, IL-6) and pharmacological agents (5-amino-4-imidazolecarboxamide ribonucleoside AICAR and metformin). Phosphorylation of acetyl-CoA carboxylase 2 (ACC2) at S221 (S212 in mice) by AMPK reduces ACC activity and malonyl-CoA content but the importance of the AMPK–ACC2–malonyl-CoA pathway in controlling fatty acid metabolism and insulin sensitivity is not understood; therefore, we characterised
Acc2
S212A knock-in (ACC2 KI) mice.
Methods
Whole-body and skeletal muscle fatty acid oxidation and insulin sensitivity were assessed in ACC2 KI mice and wild-type littermates.
Results
ACC2 KI mice were resistant to increases in skeletal muscle fatty acid oxidation elicited by AICAR. These mice had normal adiposity and liver lipids but elevated contents of triacylglycerol and ceramide in skeletal muscle, which were associated with hyperinsulinaemia, glucose intolerance and skeletal muscle insulin resistance.
Conclusions/interpretation
These findings indicate that the phosphorylation of ACC2 S212 is required for the maintenance of skeletal muscle lipid and glucose homeostasis.
Calcium/calmodulin-dependent protein kinase (CaMK) activation induces mitochondrial biogenesis in response to increasing cytosolic calcium concentrations. Calcium leak from the ryanodine receptor ...(RyR) is regulated by reactive oxygen species (ROS), which is increased with high-fat feeding. We examined whether ROS-induced CaMKII-mediated signaling induced skeletal muscle mitochondrial biogenesis in selected models of lipid oversupply. In obese Zucker rats and high-fat-fed rodents, in which muscle mitochondrial content was upregulated, CaMKII phosphorylation was increased independent of changes in calcium uptake because sarco(endo)plasmic reticulum Ca(2+)-ATPase (SERCA) protein expression or activity was not altered, implicating altered sarcoplasmic reticulum (SR) calcium leak in the activation of CaMKII. In support of this, we found that high-fat feeding increased mitochondrial ROS emission and S-nitrosylation of the RyR, whereas hydrogen peroxide induced SR calcium leak from the RyR and activation of CaMKII. Moreover, administration of a mitochondrial-specific antioxidant, SkQ, prevented high-fat diet-induced phosphorylation of CaMKII and the induction of mitochondrial biogenesis. Altogether, these data suggest that increased mitochondrial ROS emission is required for the induction of SR calcium leak, activation of CaMKII, and induction of mitochondrial biogenesis in response to excess lipid availability.
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