# Exercise as it relates to Disease/Effect of exercise on adiponectin in improving insulin sensitivity
## What is Adiponectin (Ad)?

Adiponectin (Ad) is an adipocyte-derived protein with anti-inflammatory properties and is important for glucose and lipid metabolism. The exact mechanisms involved in the physiological processes of Ad are largely unknown. It is relatively abundant in healthy humans at levels of 2–10 mg/ml. Ad is found in lower concentrations in individuals with:
* Coronary artery disease
* Type 2 diabetes and/or insulin resistance
* High BMI and/or percentage body fat
Decreasing adipose tissue has been shown to increase Ad levels.
However, individuals with higher adiposity are likely to have increased levels of the Ad receptors, AdipoR1 and AdipoR2, which may be a compensatory mechanism.

## The Response of Exercise and Ad in Increasing Insulin Sensitivity

Hypoadiponectinemia is associated with insulin resistance and type 2 diabetes and is a biomarker for assessment of lifestyle changes. Higher levels of Ad have been shown to increase insulin sensitivity through similar mechanisms as the potent effect of exercise muscle contractions in enhancing the insulin-signaling pathway. This is shown in Table 1 and highlights the potential for exercise to enhance the action of Ad when combined.
Table 1: Mechanisms by which Ad and Exercise Increase Insulin Sensitivity
| Mechanism | Adiponectin | Exercise |
| Increase muscle and liver triglycerides | ✔ | ✔ |
| Activation of Ca2+/ AMPK pathways and deactivation of ACC | ✔ | ✔ |
| Up-regulation of PGC1a | ✔ | ✔ |
| Stimulates glucose transport via GLUT4 translocation | ✔ | ✔ |
| Increase insulin-induced phosphorylation of insulin receptor substrate 1 and Akt | ✔ | |
| Potentially inhibiting the negative effects of TNF-α on insulin action | ✔ | |
| Increase catecholamines | | ✔ |

## The Impact of Exercise on Ad Secretion

Studies have been conducted on obese, healthy and diabetic individuals and have resulted in disparate conclusions in regards to the effect of exercise on Ad in improving inulin sensitivity. Studies report increases, decreases and no change in Ad levels in response to various acute and chronic exercise programs. This is displayed in Table 2.
Table 2: Effect of Different Exercise on Ad Secretion
| Type of Exercise | Acute | Chronic |
| Strenuous intermittent running/HIIT | No change | Increase |
| Elite athlete maximal row | Decrease | Increase |
| Submaximal aerobic exercise | No change, Increase | No change, Increase |
| Endurance Exercise | No change | No change |
| Intensive aerobic training program | No change, Increase | No change, Increase |
Increases in Ad levels may be explained by:
* A reduction in body fat, which could account for the increase rather than adaptive measures to exercise.
* Adipocytes preforming stores of Ad, which are released in response to exercise.
No change in Ad levels may be explained by:
* Increases of beta-adrenergic, glucocorticoid, insulin, interleukin-6 and catecholamine activity that is associated with moderate to intense exercise which may impede Ad and Ad gene expression. This could be a protective mechanism to avoid excessive decreases in glycemia from exercise.
Numerous studies show increases in insulin sensitivity without exhibiting increases in Ad levels, indicating that improvements in insulin sensitivity are not dependent on increases in Ad levels. This suggests that there are other mechanisms involved. One such proposal is an up-regulation of the Ad receptors, AdipoR1 and AdipoR2, in response to exercise.

## Up-regulation of Ad Receptors

An up-regulation of Ad receptor density in the muscle, more specifically AdipoR1, through acute and chronic exercise increases insulin sensitivity without the requirement of an increase in Ad levels. This achieves the targeted mechanisms and may explain the contradicting findings of the previous section.

## Recommendations

There are two known approaches towards increasing the affect of Ad on insulin sensitivity through exercise:
* Exercise that is favourable for body fat loss is shown to naturally increase Ad secretion. Aerobic/endurance steady state exercise combined with reduced calorie intake would be sufficient.
* Acute intensive training and general chronic exercise is shown to increase Ad receptor expression.

## Further Resources

* Diabetes Care Journa- Exercise Increases Adiponectin and Insulin Sensitivity & Insulin Resistance by Adiponectin Deficiency: Is the Action in Skeletal Muscle?
* Adiponectin and Adiponectin Receptors in Insulin Resistance, Diabetes, and the Metabolic Syndrome
* Adiponectin: A Fat Cell Hormone that Promotes Insulin Sensitivity

## References

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* 1 2 3 4 5 6 7 Højbjerre, L, Rosenzweig, M, Dela, F, Bruun, JM & Stallknecht, B 2007, ‘Acute exercise increases adipose tissue interstitial adiponectin concentration in healthy overweight and lean subjects’, European Journal of Endocrinology, vol. 157, pp. 613-623.
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* 1 2 3 4 Boudou, P, Sobngwi, E, Mauvais-Jarvis, F, Vexiau, P & Gautier, JF 2003, ‘Absence of exercise-induced variations in adiponectin levels despite decreased abdominal adiposity and improved insulin sensitivity in type 2 diabetic men’, European Journal of Endocronolgy, vol. 149, pp. 421-424.
* 1 2 3 4 5 Yatagai, T et al. 2003, ‘Relationship between exercise training-induced increase in insulin sensitivity and adiponectinemia in healthy men’, Endocrine Journal, vol. 50, no. 2, pp. 233-238.
* 1 2 3 Ritchie, IR, Wright, DC & Dyck, DJ 2014, ‘Adiponectin is not required for exercise training-induced improvements in glucose and insulin tolerance in mice’, Physiological Reports, vol. 2, no. 9, doi: 10.14814/phy2.12146
* ↑ Yamauchi, T et al. 2002, ‘Adiponectin stimulates glucose utilization and fatty-acid oxidation by activating AMP-activated protein kinase’, Nature Medicine, vol. 8, pp. 1288-1295.
* 1 2 3 Passos, MCF & Goncalves, MC 2014, ‘Regulation of insulin sensitivity by adiponectin and its receptors in response to physical exercise’, Hormone and Metabolic Research, vol. 46, no. 9, pp. 603-608, doi: 10.1055/s-0034-1377026
* 1 2 3 4 Kriketos, AD, Gan, S, Poynten, AM, Furler, SM, Chisholm, DJ & Campbell, LV 2004, ‘Exercise Increases Adiponectin Levels and Insulin Sensitivity in Humans’, Diabetes Care, vol. 27, no. 2, pp. 629-630, doi: 10.2337/diacare.27.2.629
* ↑ Racil, G et al. 2013, ‘Effects of high vs. moderate exercise intensity during interval training on lipids and adiponectin levels in obese young females’, European Journal of Applied Physiology, vol. 113, no. 10, pp. 2531-2540.
* ↑ Marcell, TJ, McAuley, KA, Traustadttir, T & Reaven, PD 2005, ‘Exercise training is not associated with improved levels of C-reactive protein or adiponectin’, Metabolism-Clinical and Experimental, vol. 54, no. 4, pp. 533-541.
* ↑ Nassis, GP et al. 2005, ‘Aerobic exercise training improves insulin sensitivity without changes in body weight, body fat, adiponectin, and inflammatory markers in overweight and obese girls’, Metabolism-Clinical and Experimental, vol. 54, no. 11, pp. 1472-1479.
* ↑ Kelly, KR et al. 2012, ‘A 7-day exercise program increases high-molecular weight adiponectin in obese adults’, Medicine and Science in Sports and Exercise, vol. 44, no. 1, pp. 69-74.
* 1 2 Hulver, MW et al. 2002, ‘Adiponectin is not altered with exercise training despite enhanced insulin action’, American Journal of Physiology, vol.283, no. 4, pp. 861-865.