Autophagy alterations in obesity, type 2 diabetes, and metabolic dysfunction-associated steatotic liver disease: the evidence from human studies

Abstract

Autophagy is an evolutionarily conserved process that plays a pivotal role in the maintenance of cellular homeostasis and its impairment has been implicated in the pathogenesis of various metabolic diseases including obesity, type 2 diabetes (T2D), and metabolic dysfunction-associated steatotic liver disease (MASLD). This review synthesizes the current evidence from human studies on autophagy alterations under these metabolic conditions. In obesity, most data point to autophagy upregulation during the initiation phase of autophagosome formation, potentially in response to proinflammatory conditions in the adipose tissue. Autophagosome formation appears to be enhanced under hyperglycemic or insulin-resistant conditions in patients with T2D, possibly acting as a compensatory mechanism to eliminate damaged organelles and proteins. Other studies have proposed that prolonged hyperglycemia and disrupted insulin signaling hinder autophagic flux, resulting in the accumulation of dysfunctional cellular components that can contribute to β-cell dysfunction. Evidence from patients with MASLD supports autophagy inhibition in disease progression. Nevertheless, given the available data, it is difficult to ascertain whether autophagy is enhanced or suppressed in these conditions because the levels of autophagy markers depend on the overall metabolism of specific organs, tissues, experimental conditions, or disease duration. Owing to these constraints, determining whether the observed shifts in autophagic activity precede or result from metabolic diseases remains challenging. Additionally, autophagy-modulating strategies are shortly discussed. To conclude, more studies investigating autophagy impairment are required to gain a more comprehensive understanding of its role in the pathogenesis of obesity, T2D, and MASLD and to unveil novel therapeutic strategies for these conditions.

Keywords: Autophagy modulators; Cellular quality control; Metabolic diseases; Patients; Therapies; Tissue biopsy.

Fig. 1

The primary mechanism initiating autophagy involves activation of the Unc-51-like kinase (ULK) complex, consisting of ULK1/ATG1, ATG13, FIP200, and ATG101. The key regulators of autophagy initiation are the mTORC1 complex and AMP-activated protein kinase (AMPK), which act in opposition to each other; however, both control autophagy through ULK1 phosphorylation. AMPK, the primary sensor of cellular energy state, is activated when intracellular AMP levels rise (indicating starvation) and then promotes autophagy by directly activating ULK1 through the phosphorylation of Ser317 and Ser777. Under conditions of nutrient sufficiency, mTORC1 prevents ULK1 activation by phosphorylating Ser757 on ULK1 and disrupting the interaction between ULK1 and AMPK [30, 31]. The ULK1 complex further activates the BECN1-VPS34-ATG14L-p150 complex through the phosphorylation of Beclin 1 (BECN1). Activation of the BECN1 complex leads to the generation of phosphatidylinositol-3-phosphate (PI3P), which is crucial for the nucleation of autophagic vesicles by promoting membrane elongation through the recruitment of the ATG2-WIPI (WD‐repeat protein interacting with phosphoinositides) protein complex. The elongation and maturation of autophagosomes involve two conjugation systems similar to the ubiquitination system: the microtubule-associated protein 1 light chain 3 (LC3/ATG8) system and the ATG12 system [32]. LC3 is modified by ATG4, resulting in LC3-I with an exposed glycine residue at the C-terminus. This allows the conjugation of LC3-I with ATG7 (an E1-like enzyme) and then with ATG3 (an E2-like enzyme) [23]. ATG3-LC3 is recognized by the ATG5-ATG12 complex associated with the ATG16L protein (ATG16L complex), which catalyzes the conjugation of LC3 with phosphatidylethanolamine (PE), forming insoluble LC3-II that is stably incorporated into the autophagosomal membrane [33, 34]. Interestingly, cargo selection for the autophagy process can be facilitated by adaptor proteins, such as p62/SQSTM1, which possess a ubiquitin-binding domain and an LC3-II interacting domain. The fusion of autophagosomes and lysosomes is regulated by several molecules including soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNAREs) and lysosome-associated membrane proteins (LAMPs) [21, 32]. Finally, in the last step of autophagy, the encapsulated cargo is degraded by lysosomal proteases, and the products are released back into the cytosol through lysosomal permeases [32]

Fig. 2

Autophagy-modulating strategies in obesity, type 2 diabetes (T2D) and metabolic dysfunction-associated steatotic liver disease (MASLD)