Disordered adrenergic regulation of hepatic and adipose metabolic pathways in hyperadrenergic states of aging and obesity

Aging and obesity are two inter-related risk factors for the metabolic syndrome, a widely prevalent cluster of disordered regulatory processes predisposing to atherosclerotic cardiovascular disease (ASCVD) and metabolic diseases such as type 2 diabetes mellitus (T2DM) and nonalcoholic fatty liver disease (NAFLD, recently re-designated metabolic dysfunction-associated steatotic liver disease [MASLD]). Both aging and obesity are hyperadrenergic states, characterized by increased circulating levels of catecholamines and/or over-activity of the sympathetic nervous system (SNS). Variable, tissue-specific changes in adrenergic responsive signal transduction pathways (notably via β2-adrenergic receptor [β2-AR] signaling systems) of liver and fat depots are associated with aging and obesity and have, in turn, been invoked in cellular mechanisms underlying hepatic glucose dysregulation and steatosis in senescent and obese animals. Whether altered adrenergic responses of critical target tissues occurring in hyperadrenergic states are themselves direct consequences of heightened catecholamine levels or SNS activity is yet to be determined, although recent evidence does link modified central nervous system (CNS) control of systemic sympathetic outflow to at least one disorder related to the metabolic syndrome, namely, MASLD. Other critical variables, such as organ-specific variation in SNS inputs, changes in autonomic neuropathy occurring over time, leptin-mediated neuroendocrine regulatory networks, and influences of localized immune cells on SNS regulation of adipose and liver metabolism, have been implicated in the pathogenetic mechanisms underlying elements of the metabolic syndrome. Further, interrelationships between altered adrenergic inputs and insulin resistance--the hallmark pathophysiologic characteristic of the metabolic syndrome--in critical end organs such as liver and fat have not been meaningfully investigated in hyperadrenergic states. Notwithstanding a complex, and sometimes contradictory, literature in this area, further understanding of the interplay among CNS directed circulating catecholamine levels and SNS outflow, adrenergic signaling pathways in liver and fat, and SNS/catecholaminergic mediated regulation of glucose control and hepatic fat accumulation in aging and obesity may serve to identify molecular targets applicable to treatment or prevention of T2DM, MASLD and possibly other aspects of the metabolic syndrome in vulnerable populations worldwide.This Research Topic is intended to address how modifications of circulating catecholamines, systemic or tissue-specific SNS activities, and/or adrenergic responsive signaling pathways in liver and adipose tissues may result in disordered hepatic glucose and fat metabolism occurring in aging and obesity. Original research papers and authoritative reviews will be sought in areas providing insights into adrenergic responsive processes involved in the pathophysiology of dysglycemia and MASLD in relevant animal models as well as aged and obese humans. The overall goal is to identify a continuum of aging- and obesity-related phenomena—inclusive of disordered CNS control of systemic sympathetic outflow, elevated circulating catecholamine levels, and tissue-specific alterations of SNS inputs and/or adrenergic responsive metabolic signaling pathways in liver and adipose depots—that might illuminate innovative therapeutic strategies for diabetes mellitus and MASLD.Research sub-topics to be considered include the following, non-exclusive areas:• Cellular pathways by which the CNS regulates peripheral sympathetic tone, i.e., circulating levels of catecholamines and/or systemic and tissue-specific SNS activities, and mechanisms underlying altered central control of sympathetic outflow in aging and obesity • Associations and cause-and-effect relationships between levels of circulating catecholamines/SNS over-activity and end-organ adrenergic responsiveness in hepatocytes (also possibly other metabolically active liver cell types) and fat depot-specific adipocytes in aging and obesity• Cellular and molecular mechanisms of altered adrenergic receptor-responsive signaling in liver and fat cells in hyperadrenergic states of aging and obesity (e.g., increased β2-AR mediated activation of the adenylate cyclase signaling pathway in hepatocytes, previously linked to increases in glycogenolysis and steatosis during aging)• Identification of age- and obesity-dependent intracellular signaling elements, transcription factors, enzymes, etc., that may contribute to dysregulated glucose and/or fat metabolism in hepatocytes and region-specific adipocytes in hyperadrenergic states• Contribution(s) of tissue-specific SNS inputs, temporal aspects of autonomic neuropathy, leptin/CNS/SNS regulatory circuits, and immune cell interactions with sympathetic responses in fat and liver to aging- and obesity-related metabolic dysfunction • Interrelationships between altered adrenergic inputs and insulin resistance as determinants of metabolic dysregulation in liver and fat cells under conditions of aging and obesity• Potential mechanisms by which metabolic consequences of hyperadrenergic states might relate to, or be mediated by, cellular processes (e.g., accumulation of reactive oxygen species, mitochondrial and endoplasmic reticulum unfolding responses, epigenetic dysregulation, and others) that, like circulating catecholamines/SNS activity, respond to chronic stress and have themselves been implicated in aging- and obesity-related metabolic dysfunction • Whole-organism linkages among disordered CNS regulation of SNS activities (systemic and tissue-specific) and/or peripheral catecholamine levels, adrenergic responsiveness in liver and fat cells, and dysglycemia and MASLD in aging and obesity Topic editors: Michael S. Katz, Marc R Blackman, Amrita Kamat Source: https://www.frontiersin.org/research-topics/77106/disordered-adrenergic-regulation-of-hepatic-and-adipose-metabolic-pathways-in-hyperadrenergic-states-of-aging-and-obesity