TBC1D1
TBC1 domain family member 1 [KIAA1108]
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Aging, obesity and sedentarism are among the most important predictors of cardiometabolic diseases. Aiming to reduce the impact of the combination of these three factors, we tested the therapeutic and preventive effects of exercise in aging and obese rats on the following cardiometabolic disease risk parameters: body fat, blood pressure, blood lipids, and glycemic homeostasis. Eighteen male Wistar rats (initial age = 4 months, and final age = 14 months) were randomly distributed into three aging and obese groups: sedentary, therapeutic exercise and preventive exercise. Food and caloric intake, body adiposity, muscle mass, cardiovascular parameters, biochemical markers, glycemic homeostasis, and gene expression of insulin-dependent, insulin-independent and insulin resistance pathways in skeletal muscle were evaluated. Therapeutic and preventive exercises were associated with higher food and caloric intake, and expression of TBC1D1 in the soleus muscle, as well as lower total cholesterol/HDL and LDL/HDL ratios, glucose levels at the end (90 min) of the glucose tolerance test and IKBKB expression in the gastrocnemius and soleus muscles. Only the preventive exercise improved the cardiovascular and body composition parameters, glucose tolerance, insulin resistance and insulin sensitivity, besides reducing total cholesterol, triglycerides, triglycerides/HDL ratio, plasmatic insulin and MAPK8 expression in soleus. The preventive exercise group also presented greater expression of INRS, IRS1, IRS2, PIK3CA, AKT1, and SLC2A4 in gastrocnemius and soleus, TBC1D1 in gastrocnemius, and AKT2 and PRKAA1 in soleus. Therapeutic exercise promoted some improvements on cardiometabolic parameters in aging and obese rats, however, the best benefits were achieved through the preventive exercise.
MeSH Terms
- AMP-Activated Protein Kinases
- Adipose Tissue
- Adiposity
- Aging
- Animals
- Blood Glucose
- Blood Pressure
- Body Composition
- Cardiovascular Diseases
- Cholesterol
- Disease Models, Animal
- Exercise Therapy
- Glucose Tolerance Test
- Homeostasis
- Insulin
- Insulin Resistance
- Lipids
- Lipoproteins, HDL
- Male
- Metabolic Diseases
- Mitogen-Activated Protein Kinase 8
- Muscle, Skeletal
- Obesity
- Physical Conditioning, Animal
- Proteins
- Proto-Oncogene Proteins c-akt
- Rats
- Rats, Wistar
- Triglycerides
Keywords
- Aerobic exercise
- Aging
- Insulin resistance
- Metabolic Diseases
- Obesity
Skeletal muscle insulin resistance is associated with many common age-related diseases, but moderate calorie restriction (CR) can substantially elevate glucose uptake by insulin-stimulated skeletal muscle from both young and old rats. The current study evaluated the isolated epitrochlearis muscle from ∼24.5-mo-old rats that were either fed ad libitum (AL) or subjected to CR (consuming ∼65% of ad libitum, AL, intake beginning at ∼22.5 mo old). Some muscles were also incubated with MK-2206, a potent and selective Akt inhibitor. The most important results were that in isolated muscles, CR vs. AL resulted in 1) greater insulin-stimulated glucose uptake 2) that was accompanied by significantly increased insulin-mediated activation of Akt2, as indicated by greater phosphorylation on both Thr(309) and Ser(474) along with greater Akt2 activity, 3) concomitant with enhanced phosphorylation of several Akt substrates, including an Akt substrate of 160 kDa on Thr(642) and Ser(588), filamin C on Ser(2213) and proline-rich Akt substrate of 40 kDa on Thr(246), but not TBC1D1 on Thr(596); and 4) each of the CR effects was eliminated by MK-2206. These data provide compelling new evidence linking greater Akt2 activation to the CR-induced elevation of insulin-stimulated glucose uptake by muscle from old animals.
MeSH Terms
- Adaptor Proteins, Signal Transducing
- Age Factors
- Aging
- Animals
- Caloric Restriction
- Crosses, Genetic
- Deoxyglucose
- Enzyme Activation
- Filamins
- GTPase-Activating Proteins
- Insulin
- Insulin Resistance
- Male
- Muscle, Skeletal
- Phosphorylation
- Protein Kinase Inhibitors
- Proto-Oncogene Proteins c-akt
- Rats, Inbred BN
- Rats, Inbred F344
- Time Factors
Keywords
- aging
- glucose transport
- insulin resistance
- insulin signaling
Exercise and calorie restriction (CR) can each improve insulin sensitivity in older individuals, but benefits of combining these treatments on skeletal muscle insulin signaling and glucose uptake are poorly understood, especially in predominantly slow-twitch muscles (eg, soleus). Accordingly, our purpose was to determine independent and combined effects of prior acute exercise and CR (beginning at 14 weeks old) on insulin signaling and glucose uptake in insulin-stimulated soleus muscles of 30-month-old rats. CR alone (but not exercise alone) versus ad libitum sedentary controls induced greater insulin-stimulated glucose uptake. There was a main effect of diet (CR > ad libitum) for insulin-stimulated Akt(Ser473) and Akt(Thr308) phosphorylation. CR alone versus ad libitum sedentary increased Akt substrate of 160 kDa (AS160) Ser(588) phosphorylation and TBC1D1 Thr(596), but not AS160 Thr(642) phosphorylation or abundance of GLUT4, GLUT1, or hexokinase II proteins. Combined CR and exercise versus CR alone did not further increase insulin-stimulated glucose uptake although phosphorylation of Akt(Ser473), Akt(Thr308), TBC1D1(Thr596), and AMPK(Thr172) for the combined group exceeded values for CR and/or exercise alone. These results revealed that although the soleus was highly responsive to a CR-induced enhancement of insulin-stimulated glucose uptake, the exercise protocol did not elevate insulin-stimulated glucose uptake, either alone or when combined with CR.
MeSH Terms
- Aging
- Animals
- Caloric Restriction
- Disease Models, Animal
- Glucose
- Glucose Transport Proteins, Facilitative
- Insulin
- Insulin Resistance
- Male
- Muscle, Skeletal
- Physical Conditioning, Animal
- Physical Exertion
- Rats
- Rats, Inbred F344
- Signal Transduction
Keywords
- Dietary restriction
- Glucose transport
- Glucose transporter
- Insulin resistance
- Physical activity
The objective of this study was to investigate the effects of sex and slaughter age of chickens on fatty acid composition and TBC1D1 gene expression in 4 different tissues: breast muscle, thigh muscle, abdominal fat, and subcutaneous fat. Sixty Erlang mountainous chickens (hybrid SD02 x SD03) were raised under the same conditions and slaughtered at 8, 10, and 13 weeks of age. The results showed that the sex of the animal significantly affected the content of arachidic acid (C20:0), sinapic (C22:1), linoleic (C18:2n-6), eicosapentaenoic (C20:5n-3), and docosahexaenoic acids (C22:6n-3), whereas other fatty acid contents were not affected. Age had a significant effect on most monounsaturated fatty acids, except for octadecenoic acid (C18:1). TBC1D1 mRNA was abundant in all tissues at all 3 ages of slaughter. Cocks exhibited higher TBC1D1 mRNA levels than hens in the thigh muscle and abdominal fat at 10 and 13 weeks, respectively.
MeSH Terms
- Aging
- Animals
- Chickens
- Fatty Acids
- Female
- GTPase-Activating Proteins
- Gene Expression Regulation, Developmental
- Male
- Muscles
- RNA, Messenger
- Sex Characteristics
The 5'-AMP-activated protein kinase (AMPK) is considered "a metabolic master-switch" in skeletal muscle reducing ATP- consuming processes whilst stimulating ATP regeneration. Within recent years, AMPK has also been proposed as a potential target to attenuate insulin resistance, although the exact role of AMPK is not well understood. Here we hypothesized that mice lacking α2AMPK activity in muscle would be more susceptible to develop insulin resistance associated with ageing alone or in combination with high fat diet. Young (∼4 month) or old (∼18 month) wild type and muscle specific α2AMPK kinase-dead mice on chow diet as well as old mice on 17 weeks of high fat diet were studied for whole body glucose homeostasis (OGTT, ITT and HOMA-IR), insulin signaling and insulin-stimulated glucose uptake in muscle. We demonstrate that high fat diet in old mice results in impaired glucose homeostasis and insulin stimulated glucose uptake in both the soleus and extensor digitorum longus muscle, coinciding with reduced insulin signaling at the level of Akt (pSer473 and pThr308), TBC1D1 (pThr590) and TBC1D4 (pThr642). In contrast to our hypothesis, the impact of ageing and high fat diet on insulin action was not worsened in mice lacking functional α2AMPK in muscle. It is concluded that α2AMPK deficiency in mouse skeletal muscle does not cause muscle insulin resistance in young and old mice and does not exacerbate obesity-induced insulin resistance in old mice suggesting that decreased α2AMPK activity does not increase susceptibility for insulin resistance in skeletal muscle.
MeSH Terms
- AMP-Activated Protein Kinases
- Aging
- Animals
- Area Under Curve
- Blood Glucose
- Body Composition
- Diet, High-Fat
- GTPase-Activating Proteins
- Glucose Tolerance Test
- Glucose Transporter Type 4
- Hexokinase
- Homeostasis
- Insulin
- Insulin Resistance
- Male
- Mice
- Mice, Inbred C57BL
- Muscle Proteins
- Muscle, Skeletal
- Phosphorylation
- Protein Processing, Post-Translational
- Proto-Oncogene Proteins c-akt