Linseed oil improves hepatic insulin resistance in obese mice through modulating mitochondrial quality control

High-fat diet (HFD) not only induces insulin resistance in liver, but also causes autophagic imbalance and metabolic disorders, increases chronic inflammatory response and induces mitochondrial dysfunction. Calcium/calmodulin-dependent protein kinase IV (CaMKIV) has recently emerged as an important regulator of glucose metabolism and skeletal muscle insulin action. Its activation has been involved in the improvement of hepatic and adipose insulin action. But the underlying mechanism is not fully understood. In the present study, we aimed to address the direct effects of CaMKIV in vivo and to evaluate the potential interaction of impaired insulin sensitivity and autophagic disorders in hepatic insulin resistance. Our results indicated obese mice receiving CaMKIV showed decreased blood glucose and serum insulin and improved insulin sensitivity as well as increased glucose tolerance compared with vehicle injection. Meanwhile, defective hepatic autophagy activity, impaired insulin signaling, increased inflammatory response and mitochondrial dysfunction in liver tissues which are induced by high-fat diet were also effectively alleviated by injection of CaMKIV. Consistent with these results, the addition of CaMKIV to the culture medium of BNL cl.2 hepatocytes markedly restored palmitate-induced hepatic insulin resistance and autophagic imbalance. These effects were nullified by blockade of cyclic AMP response element-binding protein (CREB), indicating the causative role of CREB in action of CaMKIV. Our findings suggested that CaMKIV restores hepatic autophagic imbalance and improves impaired insulin sensitivity via phosphorylated CREB signaling pathway, which may offer novel opportunities for treatment of obesity and diabetes.

Download Full-text

EFFECTS OF HIGH-INTENSITY INTERVAL TRAINING ON SKELETAL MUSCLE MITOCHONDRIAL QUALITY CONTROL IN DIET-INDUCED OBESE MICE

Medicine & Science in Sports & Exercise ◽

10.1249/01.mss.0000760508.99846.bd ◽

2021 ◽

Vol 53 (8S) ◽

pp. 117-117

Author(s):

Kai Zou ◽

James B. Tincknell ◽

Benjamin A. Kugler ◽

Haley Spicuzza ◽

Paul Nguyen ◽

...

Keyword(s):

Skeletal Muscle ◽

Quality Control ◽

High Intensity ◽

Interval Training ◽

Obese Mice ◽

High Intensity Interval Training ◽

Mitochondrial Quality Control ◽

High Intensity Interval

Download Full-text

OR-043 UPRmt and mitophagy are selectively activated depending on muscle fiber types in insulin resistant rats

Exercise Biochemistry Review ◽

10.14428/ebr.v1i2.9723 ◽

2018 ◽

Vol 1 (2) ◽

Author(s):

Can Li ◽

Nan Li ◽

Yong Zhang

Keyword(s):

Insulin Resistance ◽

Skeletal Muscle ◽

Quality Control ◽

Muscle Fiber ◽

Slow Muscle ◽

Muscle Fiber Types ◽

Fiber Types ◽

Mitochondrial Quality Control ◽

Insulin Resistant ◽

Related Proteins

Objective To investigate how different skeletal muscle fiber types affect development of insulin resistance, and to explore the role of mitochondrial quality control system, especially mitochondrial unfolded protein response (UPRmt) and mitophagy, in response to metabolic stresses. Methods Male Wistar rats were randomly divided into 2 groups: fed with the normal diet for 8 weeks (Con), and fed with 45% high-fat diet for 8 weeks (IR). Fasting blood glucose (FBG), fasting insulin (FIN) and oral glucose tolerance test (OGTT) were used to identify insulin resistance model. Gastrocnemius (GC), soleus (SOL) and tibialis anterior (TA) muscle were isolated, and RT-qPCR was used to determine the expression of Myhc7, Myhc4. Oxygraph-2k was used to determine the mitochondrial State 3 (ST3), State 4(ST4) respiration and respiration control rate (RCR). JC-1 probe was used to measure mitochondrial membrane potential. Western Blot was used to determine the expressions of marker proteins of muscle fiber types (Myhc4, Myhc7), UPRmt related proteins (Hsp60, Hsp70) and mitophagy related proteins (Pink1, LC3). Results Compared with Con group, in IR group, FBG (7.1±1.27 vs. 5.4±0.43，p＜0.05), FIN (19.4±5.2 vs. 31.6±6.7，p＜0.05 ) and OGTT (area under the curve, about 31.7% increases, p＜0.05) were significantly higher. Myhc4 mRNA (relative fold about 55.6% increases) and protein expression (about 33.9% increases, p＜0.05) were significantly higher in GC. Myhc4 protein expression was significantly higher in GC (about 60.5% increases, p＜0.05). While Myhc7 mRNA expression (about 51.1% decreases, p＜0.05) was significantly lower in SOL. Compared with Con group, in IR group, mitochondrial RCR in SOL muscle was significantly lower (about 22.5% decreases, p＜0.05). Furthermore, the expression of HSP60 (about 36.7% increases，p＜0.05) and HSP70 (about 44.3% increases，p＜0.05) was significantly higher in TA muscle, while the expression of Parkin (about 18.8% decreases，p＜0.05) and the ratio between LC3 II/I (about 26.0% decreases，p＜0.05)expression in SOL muscle were significantly lower. Conclusions In this study, we found that the percentage of fast muscle fibers was elevated in IR skeletal muscle, which were supported by increased Myhc4 and decreased Myhc7 level. Impaired mitochondrial function was only observed in slow muscle as inhibition of mitochondrial respiration. As marker of UPRmt, HSP60/70 were specifically activated in fast muscle in IR, while mitophagy-related proteins were specifically increased in slow muscle. These results indicate that mitochondrial quality control systems are selectively activated to recover mitochondrial functions depending on muscle fiber types in insulin resistant rat.

Download Full-text

Anti-insulin resistance effects of salidroside through mitochondrial quality control

Journal of Endocrinology ◽

10.1530/joe-19-0393 ◽

2020 ◽

Vol 244 (2) ◽

pp. 383-393 ◽

Cited By ~ 2

Author(s):

Baiyang You ◽

Yaoshan Dun ◽

Wenliang Zhang ◽

Lingjun Jiang ◽

Hui Li ◽

...

Keyword(s):

Insulin Resistance ◽

Quality Control ◽

Critical Issue ◽

C2c12 Myotubes ◽

Blood Levels ◽

Ros Production ◽

Mitochondrial Quality Control ◽

Beneficial Effects ◽

Compound C ◽

And Function

Mitochondrial quality control (MQC) and function are determinants for cellular energy metabolism, and their disorders are reported to play an important role in the development of insulin resistance (IR). Salidroside was reported to have beneficial effects on MQC through AMPK pathway; however, it is unknown whether salidroside exerts anti-IR effect with this action. This study sought to investigate the effects of salidroside on IR with an exploration of the mechanisms of its action. Experimental IR models were adopted in high-fat-diet (HFD)-fed mice and palmitate-treated C2C12 myotubes, respectively. Blood levels of glucose and insulin as well as cellular glucose uptake were determined, and mitochondrial function and MQC-associated parameters and reactive oxygen species (ROS) production were analyzed based on treatments with the activator (AICAR), inhibitors (compound C and EX-527) or specific siRNA of Ampk/Sirt1 and mitochondrial ROS scavenger (mito-TEMPO). Protein expression level was determined by Western blot, cellular observation by transmission electron microscope and ROS production by functional analysis kits. Salidroside reduced IR and activated insulin signaling along with the stimulation of AMPK/SIRT1 signaling and downstream regulation of MQC and ROS production. These salidroside effects were comparable to those of AICAR and could be prevented by AMPK/SIRT1 inhibitors or siRNAs, respectively. Salidroside reduces IR and regulates MQC and ROS production by activating AMPK/SIRT1 signaling pathway. Since IR is a critical issue for public health, to explore a potent agent against IR is of high interest. The anti-IR effects of salidroside warrant further experimental and clinical studies.

Download Full-text