The Role of Exercise in the Interplay between Myokines, Hepatokines, Osteokines, Adipokines, and Modulation of Inflammation for Energy Substrate Redistribution and Fat Mass Loss: A Review

Abstract

Exercise is an effective strategy for preventing and treating obesity and its related cardiometabolic disorders, resulting in significant loss of body fat mass, white adipose tissue browning, redistribution of energy substrates, optimization of global energy expenditure, enhancement of hypothalamic circuits that control appetite-satiety and energy expenditure, and decreased systemic inflammation and insulin resistance. Novel exercise-inducible soluble factors, including myokines, hepatokines, and osteokines, and immune cytokines and adipokines are hypothesized to play an important role in the body's response to exercise. To our knowledge, no review has provided a comprehensive integrative overview of these novel molecular players and the mechanisms involved in the redistribution of metabolic fuel during and after exercise, the loss of weight and fat mass, and reduced inflammation. In this review, we explain the potential role of these exercise-inducible factors, namely myokines, such as irisin, IL-6, IL-15, METRNL, BAIBA, and myostatin, and hepatokines, in particular selenoprotein P, fetuin A, FGF21, ANGPTL4, and follistatin. We also describe the function of osteokines, specifically osteocalcin, and of adipokines such as leptin, adiponectin, and resistin. We also emphasize an integrative overview of the pleiotropic mechanisms, the metabolic pathways, and the inter-organ crosstalk involved in energy expenditure, fat mass loss, reduced inflammation, and healthy weight induced by exercise.

Keywords: adipokines; energy substrate redistribution; exercise; fat mass loss; hepatokines; inflammation; myokines; obesity; osteokines; physical activity.

Figure 1

Effects of exercise-inducible factors on appetite control. Details in text. Abbreviations: BAIBA: β-Aminoisobutyric acid; EE: Energy expenditure; FGF21: Fibroblast-growth factor 21; FI: Food intake; GLP-1: Glucagon-like peptide 1; IL-6: Interleukin-6; OCN: Osteocalcin. Green arrows represent a stimulatory effect over another mediator; red inhibitor lines represent an inhibitory effect over another mediator; black arrows or inhibitor lines indicate the final physiologic effect of any given mediator, either stimulatory or inhibitory, respectively. Custom image created with Biorender.

Figure 2

Effects of exercise-inducible factors on the systemic inflammatory milieu and insulin sensitivity. Details in text. Abbreviations: BAIBA: β-Aminoisobutyric acid; FGF21: Fibroblast growth factor 21; IL-1Ra: Interleukin-1 receptor antagonist; IL-1β: Interleukin-1β; IL-6: Interleukin-6; IL-10: Interleukin-10; IL-15: Interleukin-15 MCP-1: Monocyte chemoattractant protein-1; METRNL: Meteorin-like; OCN: Osteocalcin; TNF-α: Tumor necrosis factor-alpha. Green arrows represent a stimulatory effect over another mediator; red inhibitor lines represent an inhibitory effect over another mediator; black arrows or inhibitor lines indicate the final physiologic effect of any given mediator, either stimulatory or inhibitory, respectively; dotted lines indicate absence of an expected effect, either stimulatory or inhibitory. Custom image created with Biorender.

Figure 3

Effects of exercise-inducible factors on WAT “browning”. Details in text. Abbreviations: BAIBA: β-Aminoisobutyric acid; BAT: Brown (and beige) adipose tissue; FGF21: Fibroblast growth factor 21; GLP-1: Glucagon-like peptide 1; IL-6: Interleukin-6; IL-15: Interleukin-15; METRNL: Meteorin-like; OCN: Osteocalcin; SNS: Sympathetic nervous system; WAT: White adipose tissue. Green arrows represent a stimulatory effect over another mediator; red inhibitor lines represent an inhibitory effect over another mediator; black arrows or inhibitor lines indicate the final physiologic effect of any given mediator, either stimulatory or inhibitory, respectively; dotted lines indicate absence of an expected effect, either stimulatory or inhibitory. Custom image created with Biorender.

Figure 4

Effects of exercise-inducible factors on hepatic and SkM FAO, WAT lipolysis, and hepatic lipogenesis. Details in text. *Although SeP is not regulated by exercise, its high concentrations in obesity might impair SkM adaptation to oxidative metabolism. Abbreviations: ANPTL4: Angiopoietin-like 4; BAIBA: β-Aminoisobutyric acid; FAO: Fatty acid oxidation; FFAs: Free fatty acids; FGF21: Fibroblast growth factor 21; IL-6: Interleukin-6; IL-15: Interleukin-15; IR: Insulin resistance; METRNL: Meteorin-like; OCN: Osteocalcin; SeP: Selenoprotein P; TG: Triglycerides; VLDL: Very-low-density lipoprotein. Green arrows represent a stimulatory effect over another mediator; red inhibitor lines represent an inhibitory effect over another mediator; black arrows or inhibitor lines indicate the final physiologic effect of any given mediator, either stimulatory or inhibitory, respectively; dotted lines indicate absence of an expected effect, either stimulatory or inhibitory. Custom image created with Biorender.

Figure 5

An integrated view of the role of exercise training on pathways associated with energy expenditure, fat mass loss, redistribution of energy substrates, adipose tissue reserves, and immunometabolic health: integrated neuroendocrine pathways associated with exercise training that affect global AT reserves and function. Interdependence between the processes of central control of energy balance, WAT browning, inflammation, and insulin sensitivity is highlighted. AT: adipose tissue, ANGPTL4: Angiopoietin-like 4; BAIBA: β-Aminoisobutyric acid; BAT: Brown (and beige) adipose tissue; EE: Energy expenditure; ER: Endoplasmic reticulum; FAO: Fatty acid oxidation; FI: Food intake; FGF21: Fibroblast growth factor 21; GH: Growth hormone; GLP-1: Glucagon-like peptide 1; IL-1Ra: Interleukin-1 receptor antagonist; IL-1β: Interleukin-1β; IL-6: Interleukin-6; IL-10: Interleukin-10 IL-15: Interleukin-15; MCP-1: Monocyte chemoattractant protein-1; METRNL: Meteorin-like; OCN: Osteocalcin; OS: Oxidative stress; ROS: Reactive oxygen species; SNS: Sympathetic nervous system; TNF-α: Tumor necrosis factor alpha; VAT: Visceral adipose tissue. Green arrows represent a stimulatory effect over another mediator; red inhibitor lines represent an inhibitory effect over another mediator; black arrows or inhibitor lines indicate the final physiologic effect of any given mediator, either stimulatory or inhibitory, respectively; blue arrow or inhibitor lines indicate the consequence of a process as a whole, either stimulatory or inhibitory, respectively; orange inhibitor lines indicate the final processes in the control of fat mass; dotted lines indicate absence of an expected effect, either stimulatory or inhibitory. Custom image created with Biorender.