Using LC to Measure Aerobic Exercise's Impact on Insulin Resistance in Obesity

Emerging evidence has suggested that the disrupted branched-chain amino acids (BCAAs) homeostasis and elevated BCAAs promote obesity-related insulin resistance (IR). While exercise improves insulin sensitivity, whether BCAAs plays a role in the exercise-attenuated IR remains to be fully investigated. To that end, researchers have recently published a paper in Frontiers in Nutrition (1) showing that 12-week aerobic exercise reduced circulating BCAAs level in obese mice while attenuating insulin resistance. Plasma BCAAs and branched-chain keto acids (BCKAs) of the test subjects were measured with a liquid chromatography (LC) system coupled to an electrospray-ionization triple-quadrupole mass spectrometer (TQMS).

The research team found that aerobic exercise also induced the expression of BCAAs catabolic protein in the skeletal muscles and livers. More importantly, supplementation of BCAAs in drinking water counteracted the effects of exercise on BCAAs and insulin sensitivity. These data demonstrated that aerobic exercise attenuated IR via restoring BCAAs homeostasis, and BCAAs or protein nutritional intake could tune the metabolic benefits of exercise.

Obesity, non-alcoholic fatty liver disease, type 2 diabetes, and other metabolic diseases represent a major worldwide public health challenge (2). Physical activity and exercise have been recognized as non-pharmacological interventions for metabolic disorders, including diabetes and IR (3-6), a condition in which the body’s tissues and organs show a reduced biological action of insulin (7). A major pathophysiological factor in the development and progression of Type 2 diabetes, IR is also strongly associated with numerous metabolic disorders (8).

Five-week-old male mice, after one week of normal chow feeding for acclimatization, were then fed a high-fat diet with a ratio of 60% fat for 12-week to induce obesity (DIO). For the first experiment, DIO mice were randomly divided into sedentary group (CON, n = 16) and exercise group (EX, n = 16). The EX group undertook a 12-week aerobic exercise on a treadmill. Plasma BCAAs and BCKAs were measured, and glucose tolerance test (GTT) and insulin tolerance test (ITT) were performed after a 12-week period. At 48-h after the last exercise, subgroups from each group (n = 8) were administered an injection of either insulin solution or saline, and gastrocnemius muscle and liver tissues were sampled after 10-min of rest for further analysis (1).

In the second experiment, DIO mice were randomly allocated into 4 groups: sedentary group (CON, n = 8), sedentary with BCAAs supplementation group (CON+BCAA, n = 8), exercise group (EX, n = 16), and exercise with BCAAs supplementation group (EX+BCAA, n = 16). Plasma BCAAs and BCKAs were measured, and GTT and ITT tests were performed after 12-week. At 48-h after the last exercise, subgroups (n = 8) from EX and EX+BCAA groups were administered an injection of either insulin solution or saline, respectively, and gastrocnemius muscle and liver tissues were sampled after 10-min of rest for further analysis (1).

As expected, aerobic exercise attenuated IR in DIO mice, with 12-week aerobic exercise significantly improving and insulin tolerance. While exercise effectively reduced body weight, it did not induce significant alterations in the body composition of the mice. In addition, exercise significantly enhanced the insulin-induced phosphorylation of Protein Kinase B (AKT) at T308 in skeletal muscle and liver (1).

The authors believe that their work shows that long-term aerobic exercise reduces the circulating BCAAs to improve insulin sensitivity in DIO mice, unraveling a mechanism underlying the beneficial effects of exercise. In addition, the influences of dietary BCAAs intake on exercise-attenuated IR suggest that nutritional protein intake may affect the therapeutic effects of exercise, highlighting the combined exercise and nutrition intervention strategy for diabetes management. Furthermore, exercise boosted AMP-activated protein kinase (AMPK) activity, inhibited by BCAAs supplementation, implying the role of AMPK in the exercise-BCAAs interplay on IR (1).

Doctor measuring obese man stomach. © grinny - stock.adobe.com

References

1. Cao, W.; Liu, Y.; Wei, H.; Dong, Y.; Sun, H.; Zhang, X.; Qiu, J. Aerobic Exercise Attenuates Insulin Resistance via Restoring Branched Chain Amino Acids Homeostasis in Obese Mice. Front Nutr. 2024, 11, 1451429. DOI: 10.3389/fnut.2024.1451429

2. Blüher, M. Obesity: Global Epidemiology and Pathogenesis. Nat. Rev. Endocrinol. 2019, 15, 288–298. DOI: 10.1038/s41574-019-0176-8

3. Jakicic, J. M.; Rogers, R. J.; Davis, K. K.; Collins, KA. Role of Physical Activity and Exercise in Treating Patients with Overweight and Obesity. Clin. Chem. 2018, 64, 99–107. DOI: 10.1373/clinchem.2017.272443

4. Sallis, R.; Franklin, B.; Joy, L.; Ross, R.; Sabgir, D.; Stone, J. Strategies for Promoting Physical Activity in Clinical Practice. Prog. Cardiovasc. Dis. 2015, 57, 375–386. DOI: 10.1016/j.pcad.2014.10.003

5. Stefani, L.; Galanti, G. Physical Exercise Prescription in Metabolic Chronic Disease. Adv. Exp. Med. Biol. 2017, 1005, 123–411. DOI: 10.1007/978-981-10-5717-5_6

6. Sampath Kumar, A.; Maiya, A. G.; Shastry, B. A.; Vaishali, K.; Ravishankar, N.; Hazari, A, et al. Exercise and Insulin Resistance in Type 2 Diabetes Mellitus: A Systematic Review and Meta-Analysis. Ann. Phys. Rehabil. Med. 2019, 62, 98–103. DOI: 10.1016/j.rehab.2018.11.001

7. Roberts, C.; Hevener, A.; Barnard, R. Metabolic Syndrome and Insulin Resistance: Underlying Causes and Modification by Exercise Training. Compr. Physiol. 2013, 3, 1–58. DOI: 10.1002/cphy.c110062

8. Czech, M. Insulin Action and Resistance in Obesity and Type 2 Diabetes. Nat. Med. 2017, 23, 804–814. DOI: 10.1038/nm.4350