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INNOSC Theranostics and
Pharmacological Sciences AMPK in metabolism, energy and aging

influence on AMPK activity. Anorexigenic hormones, Thus, reduced caloric intake is correlated with pain relief,
such as leptin, glucagon-like peptide (GLP-1), estradiol, as shown in clinical studies on patients with rheumatoid
insulin, and ciliary neurotrophic factor (CNTF), inhibit arthritis or fibromyalgia. In addition, this pain relief
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AMPK activity, while orexigenic hormones, including correlates with increased levels of endocannabinoid
ghrelin, adiponectin, glucocorticoids, cannabinoids, and mediators. Specifically, caloric restriction considerably
AgRP, stimulate it. AMPK is also involved in regulating increases the levels of anandamide (AEA) and
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thermogenesis in brown adipose tissue through its influence 2-arachydonoyl glycerol (2-AG) in certain areas of the
on the sympathetic nervous system, which in turn activates brain. Through the same mechanism, activation of AMPK
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to increase heat production, thereby contributing to body by caloric restriction increasing endocannabinoid levels
temperature regulation and energy expenditure. Estradiol is proposed to reduce nociception. However, studies
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centrally binds to α-type estrogen receptors, selectively suggest conflicting effects of the endocannabinoid system
decreasing AMPK activity in the ventromedial nucleus, on AMPK activity. Findings indicate a reduction in AMPK
which increases the thermogenic capacity of brown adipose activity following endocannabinoid system activation. 120,121
tissue. Variations in estradiol levels during the estrogenic Furthermore, a gradual and moderate reduction in caloric
cycle and pregnancy further modulate the AMPK pathway, intake is more effective to activate these mechanisms,
establishing its important role for in energy balance and because the sudden and drastic caloric restriction can lead
thermoregulation. 109 to unwanted effects, such as malnutrition. Intermittent
fasting has been shown in both human and animal studies
5. AMPK and the endocannabinoid system to increase levels of endocannabinoid mediators. 122

The metabolic effects associated with excess glucocorticoids In contrast to the previously mentioned approach,
are correlated with steps controlled by AMPK. As prolonged periods of moderate caloric restriction correlate
previously mentioned, activation of hypothalamic with reduced AEA and 2-AG levels. The observed
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AMPK increases appetite. In addition, there appears analgesic effect and increased 2-AG level are correlated
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to be a link between AMPK and metabolic effects with low leptin level and/or decreased leptin sensitivity. 124
involving the endocannabinoid system. These effects
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of the cannabinoid system are mediated by cannabinoid Finally, the antinociceptive response mediated by the
type 1 (CB1) receptors, which are also expressed in the endocannabinoid system during caloric restriction is
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hypothalamus. 112 attributed to an increase in the number of CB1 receptors.
Activation of hypothalamic CB1 receptors stimulates 6. Conclusion
appetite. Concurrently, glucocorticoids induce changes at Due to its central role in metabolic processes, AMPK
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the hypothalamic level that are correlated with the increase represents an important therapeutic target for the
in endocannabinoid content, suggesting an interdependence treatment and prevention of several diseases, including
between endocannabinoids, glucocorticoids, AMPK, and age-related conditions. However, questions remain
appetite regulation. However, the effects of glucocorticoids regarding its mechanism of action, activation pathways,
and cannabinoids on AMPK can vary depending on tissue and its diverse roles throughout the body. A multitude
type. For example, in the hypothalamus (stimulation) of studies consider AMPK as a metabolic “switch” that is
and adipose tissue (inhibition), the effects are the same, inactive under sufficient energy supply and activated when
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whereas in the liver and heart, they differ. In the heart, energy sources are limited. AMPK appears to coordinate
cardiac AMPK activation by cannabinoids appears to have heart metabolism through protein interactions to generate
cardioprotective effects, whereas reduced CB1 receptors targeted effects, with the goal of restoring cellular
expression is associated with negative effects. The content homeostasis. Systemic activation of AMPK, as discussed
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of endocannabinoids at the hypothalamic level varies earlier, can influence the level of the hypothalamus and
with caloric intake. During fasting, the concentration of food consumption. In addition, the existence of multiple
endocannabinoids increases, and they decrease during AMPK isoforms adds complexity, as the activation of
feeding periods, mediating both the anorexigenic effects of AMPK may benefit one organ while disadvantaging
leptin and orexigenic effects of ghrelin. 116,117 another. For example, a gain-in-function mutation in the
Caloric restriction has additional implications, γ subunit is correlated with greater glycogen storage in
particularly in modulating nociception (perception of skeletal muscles (γ ) and in the heart (γ ). This can lead
3
2
pain). Caloric restriction has been shown to modulate to glycogen storage cardiomyopathy, cardiac hypertrophy,
pain sensitivity, potentially reducing pain perception and and arrhythmias, which are disadvantages for non-athletes,
influencing the body’s response to injury or inflammation. especially athletes. It is important to note that the activation

Volume 8 Issue 2 (2025) 9 doi: 10.36922/itps.4852