Macroautophagy (hereafter referred to as autophagy) is a conserved, self-degradative, and homeostatic process, mainly involved in the recycling and degradation of cellular components including damaged organelles, aggregated or misfolded proteins, lipids, and pathogens.

When autophagy is activated a double-membraned vesicle known as the autophagosome, engulfs these cellular components and subsequently fuses with lysosomes to complete the degradation process, by involving the so-called autophagy-related proteins (ATGs), the mammalian target of rapamycin (mTOR), and the AMP-activated protein kinase (AMPK) (for review see (Zhang et al., 2018)). Figure 1 panel A depicts a simplified scheme of the autophagy process.

Autophagy is commonly recognized as a defense mechanism able to promote either cell survival or cell death by adapting its machinery to different stimuli (Sadeghi et al., 2023) including growth factors deficiencies, oxidative alterations, and metabolic changes. It is well known that autophagy is sensitive to nutrient status, and fluctuation in lipid level might serve as a physiological sensor for its regulation. Accumulating evidence suggests that autophagy is closely related to the control of energy homeostasis exerted by the hypothalamus, the brain area mainly involved in monitoring changes in the body’s energy state, by sensing alterations of key metabolic hormones and nutrients (Meng and Cai, 2011). Moreover, it is important to report that defective hypothalamic autophagy can employ changes in inflammatory pathways to exacerbate the development of obesity and metabolic disorders (Meng and Cai, 2011).

Indeed, it has been demonstrated that defects in autophagy homeostasis (an enhancement or a suppression) facilitate the onset and the development of metabolic disorders, including obesity, diabetes, and metabolic liver diseases (Kim and Lee, 2014; Zhang et al., 2018; Raza et al., 2023).

Interestingly, autophagy substrates can be preferentially sequestrated and degraded by selective types of autophagy, including lipophagy and mitophagy (Figure 1 panel B), (Zhang et al., 2018). While lipophagy is defined as the selective autophagic degradation of lipid droplets (LDs), mitophagy is a fundamental quality-control mechanism that specifically removes damaged mitochondria to maintain a functional mitochondrial network. Ectopic accumulation of fat, muscle insulin resistance, and β-cell dysfunction, the three main hallmarks occurring during obesity and type 2 diabetes mellitus (T2DM) mostly depend on the metabolic overload of mitochondria. During lipophagy triglycerides (TGs) and cholesterol are engulfed by the autophagosome and transported to lysosomes for their degradation to ultimately originate free fatty acids, which in turn, constitute fuel for mitochondrial β-oxidation. Therefore, lipophagy regulates not only intracellular lipid stores and cellular free lipids but furthermore governs cellular energy homeostasis by supporting the production of ATP. Importantly lipophagy is a selective mechanism since the quantity of lipids metabolized changes based on the extracellular source of nutrients; therefore, during an excess of nutrients (like what happens in obesity) impaired lipophagy can lead to an excess of ectopic lipid accumulation responsible for organ dysfunction and finally for cell death (for review see (Liu and Czaja, 2013)). In such conditions the β-oxidation of free fatty acid results insufficient, thus leading to the accumulation of toxic lipid intermediates which produce radical species responsible for oxidative stress associated with mitochondrial damage. The elimination of dysfunctional mitochondria via mitophagy is a process of specific importance during altered metabolic status since it allows the elimination of the vicious cycle of oxidative stress and thus counteracts the development of pathogenic processes (for review see (Sarparanta et al., 2016)).

Hence, besides autophagy, the cellular response to stressors recruits other pathways, among which the most important is inflammation. In the classic literature, inflammation is defined as the primary response of the body to address injuries. This short-term adaptive response is essential for tissue repair and involves the integration of several complex signals in distinct cells and organs. However, the extended consequences of persistent or prolonged inflammation are frequently detrimental and can alter normal physiological processes by contributing to the development of pathological chronic conditions (Hotamisligil, 2006).

A variety of studies suggest that an alteration of autophagy pathways represents an important issue in several inflammatory conditions including metabolic-related diseases (Kocak et al., 2022) and a reciprocal relationship between these two processes is crucial to orchestrate fundamental aspects of cellular and organismal responses to dangerous stimuli (Gukovsky et al., 2013; Wang et al., 2013). Indeed, several components partaking in the inflammatory cascade, including Toll-like receptors (TLRs), NOD-like receptors (NLRs), and pro-inflammatory cytokines, show the capability to activate autophagy. Conversely, also autophagy plays a regulatory role in inflammation by influencing the secretion of pro-inflammatory cytokines, the activation or inhibition of inflammasomes, and by shaping the composition of immune cells within tissues (Pang et al., 2022).

The intricate interplay between autophagy and inflammation appears crucial to orchestrate overall cellular homeostasis and efficiently respond to several challenges (Qian et al., 2017).

The present review summarizes the existing literature reporting the intricate affair between autophagy and inflammation in the context of metabolic diseases, including obesity, diabetes, and liver metabolic diseases such as non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH). The understanding of the interconnected nature of these two processes in such a context might help to identify novel pharmacological tools that might represent an attractive strategy for the treatment of obesity and other metabolic diseases.

Although the assessment of autophagy in obesity is challenging and the results reported in the literature are often controversial, a consistent number of studies report that altered autophagy has been observed in obese patients and animal models of obesity (Zhang et al., 2018). One of the most sustained hypotheses is that inhibition of autophagy enhances proinflammatory gene expression, thus suggesting that autophagy may serve to dampen inflammation and thereby limit excessive inflammatory response during obesity (Jansen et al., 2012). Most of the studies suggest that the brain’s hypothalamic area and the adipose tissue are the central stations crucial for the autophagy processes in obesity.

Diabetes represents one of the most widespread metabolic diseases worldwide and hyperglycemia is the common outcome of the two main forms of this disorder: type 1 diabetes mellitus, characterized by autoimmune destruction of pancreatic β-cells, and (T2DM), the most common, characterized by insulin resistance and a poor efficacy of insulin to control glucose homeostasis (Eizirik et al., 2020). T2DM is often associated with an exacerbation of the obese condition leading to the so-called metabolic syndrome. In this context the adipose tissue seems to be crucially involved in the production of inflammatory biomarkers, resulting from a crosstalk between immune cells, adipocytes, and macrophages that permeate it. Inflammatory response contributes to the development of T2DM by inducing insulin resistance (Lontchi-Yimagou et al., 2013). Interestingly, epidemiologic studies have suggested an association between inflammation and the occurrence of T2DM and its complications (Ruze et al., 2023). It is known that autophagy crucially contributes to the structural and functional maintenance of pancreatic islets (Yasasilka and Lee, 2024). In this context, Sidarala and collaborators suggest that mitophagy supports β cell survival and prevents the development of diabetes by dampening inflammation and that the pharmacological targeting of such pathway might potentially result in the prevention of β cell dysfunction in diabetes (Sidarala et al., 2020).

Interestingly in a state of high glucose concentration, autophagy is inhibited, and islet functions are impaired, leading to insulin resistance (Gonzalez et al., 2011). In this regard, studies have suggested that the regulation of autophagy might result in a positive outcome for the treatment of T2DM and its related pathological alterations (for review see (Zhao et al., 2023)). Specifically, in mice with a selective deletion of Atg7 in β-cells, structural alterations and reduced insulin secretion have been observed. Morphologic analysis showed an increase of ubiquitinated protein aggregates which colocalize with p62, considered a “sensor” of autophagy that drives and delivers protein aggregates to the autophagosomes (Jung et al., 2008).

In a recent paper, Park and collaborators (Park et al., 2020) by using a genetic model of mild insulin resistance, the ob/ob mice, observed an increase of hypothalamic ER stress, starting at postnatal day 10, before the development of obesity. Interestingly cells exposed to ER stress often activate autophagy and, on this line, the authors found that in vitro induction of ER stress by using tunicamycin, stimulates in the hypothalamus the autophagy-related genes Atg5, Atg7, Atg12, and p62. Interestingly the pharmacological treatment by relieving ER stress, ameliorates the glucose homeostasis, body weight, and food intake, thus highlighting the existence of an ER stress-autophagy pathway able to influence hypothalamic circuits and metabolism. Therefore, Lim and collaborators (Lim et al., 2014) showed that mice with global haploinsufficiency of the gene Atg7 (Atg7 (+/−) mice) develop diabetes when crossed with the ob/ob mice. Particularly, Atg7 (+/−)-ob/ob mice display an exacerbation of insulin resistance compared to ob/ob mice which is associated with an increase of liver lipid content and inflammatory changes (analyzed into the liver, WAT, and muscle) with activation of inflammasome. The pharmacological enhancement of autophagy flux by using imatinib or trehalose (two compounds able to enhance autophagy (Park and Lee, 2022)) results in a therapeutic effect, by improving metabolic parameters. This study strongly suggests that inhibition of systemic autophagy might impair the adaptive response to metabolic stress and might represent a causal factor in the shift from obesity to diabetes.

As an evolutionarily preserved process, autophagy can be found in all the eukaryotic cells including the hepatocytes, where, as a catabolic process, it contributes to the preservation of liver tissue homeostasis in both parenchymal (hepatocytes) and non-parenchymal (Kupffer cells, hepatic stellate cells, and sinusoidal endothelial cells) hepatic cells (Raza et al., 2023). The understanding of cell type-specific autophagy in the liver is important to develop novel focused pharmacological targets for the treatment of liver diseases. As already mentioned before in the text, autophagy participates in lipid metabolism, known as lipophagy, and interestingly mice lacking Atg7 gene or pharmacologically treated with an autophagy inhibitor show an increase in liver TGs and cholesterol (reviewed in (Ward et al., 2016)). On the same line, hepatocyte cells pharmacologically treated with an autophagy inhibitor or knockdown for the autophagy gene Atg5, show increased TGs accumulation (Singh et al., 2009a). The excessive accumulation of dietary lipids in the liver, also defined as steatosis, is responsible for disrupted hepatic lipid homeostasis with an accumulation of hepatic TGs, a typical feature of NAFLD (Giudetti et al., 2021) more recently also named metabolic dysfunction-associated steatotic liver disease. Persistent or prolonged steatosis can induce inflammatory infiltrate and hepatocyte injuries (e.g., focal necrosis and fibrosis), resulting in NASH, which can ultimately lead to advanced fibrosis, hepatic cirrhosis, and liver failure (Kořínková et al., 2020). Therefore, the regulation of excessive lipid accumulation in the hepatic tissue is crucial in the prevention or treatment of liver diseases including NAFLD and NASH. To support such a hypothesis, it has been observed an impaired autophagic flux both in the liver of a murine model of NASH and in liver biopsy of patients affected by NASH, as well as in lipid-overloaded human hepatocytes (González-Rodríguez et al., 2014). Moreover, Hammoutene et al. (Hammoutene et al., 2020) demonstrated that defective autophagy (deficiency of Atg5) in hepatic endothelial cells is associated with the promotion of liver inflammation (assessed by upregulation of cytokines including IL-6 and an increase of apoptotic markers) and fibrosis both in the early and the advanced stages of NASH. On the same line, the lack of Atg5 specifically within liver macrophages (also known as Kupffer cells) of mice exposed to HFD and treated with low-dose LPS induces a pro-inflammatory phenotype resulting in an increase of proinflammatory M1 and a decrease of anti-inflammatory M2 polarization (Liu et al., 2015). These latter studies suggest a pivotal role of Atg5 gene in the management of hepatic inflammatory state leading to the progression of liver injury.

It is well known that liver injury is responsible for hepatocyte death, leading to liver failure, hepatic fibrosis, and in the worst cases hepatocellular carcinoma; in some liver diseases including nonalcoholic and alcoholic steatohepatitis, hepatocyte death happens by a variety of mechanisms including apoptosis, necrosis, and necroptosis (Luedde et al., 2014).

NAFLD is also associated with the activity of nitric oxide synthase (NOS), and inducible NOS (INOS), two endogenous molecules often associated with liver pathological consequences, among which the promotion of lipid peroxidation and mitochondrial damage, the inhibition of hepatocyte protein synthesis and glucose homeostasis, all events which accelerate hepatocyte death. The evidence collected in a mouse model of NAFLD suggests that the liver expression of INOS is increased in macrophages and conversely the INOS knockdown decreases the macrophages number; this latter effect is associated with an improvement of autophagy observed by an increase of the autophagy-related molecules LC3 in macrophages which contribute to the maintenance of intracellular liver homeostasis during NAFLD (Jin et al., 2023).

Finally, the prevalence of NAFLD and the lack of an adequate therapy urge to also seek the identification of biomarkers of the pathology for a timelier diagnosis leading to a more efficacious pharmacological treatment. On this line, it is important to mention a very recent study published in January 2024 which comprises both preclinical and clinical evidence (Wu et al., 2024). The authors identify the upregulation of annexin 2 (ANXA2, a member of a super-family of calcium-dependent membrane binding proteins participating in a variety of fundamental biological processes, including cell survival and apoptosis) as a biomarker of NAFLD progression since its expression was increased in both the serum and the liver of patients and mice with NAFLD. By exploring the biological underpinning of such observation, the authors show that an increase of ANXA2 is stimulated by the inflammatory TLR4 cascade and negatively impacts the autophagic AMPK/mTOR pathway (Wu et al., 2024). Taken together the result of this last study underly that liver autophagy might represent the missing link between liver inflammation and the progression of liver chronic diseases.

Unhealthy lifestyle habits including a sedentary life, the lack of physical activity, and wrong dietary habits are the major ones responsible for the constant increase of metabolic disorders prevalence worldwide, and the scientific community pays significant attention to the pharmacotherapy of the treatment of such metabolic diseases (Domingo et al., 2024). In this regard, overweight and obesity represent, in most cases, the main drivers of other metabolic disorders (Godoy-Matos et al., 2020) and most of the pharmacological treatments available for obesity, T2DM, and metabolic liver injury, including NAFLD and NASH, have a mutual effect on the others, although to date NAFLD and NASH do not have a recognized selective pharmacological treatment representing an unmet medical need (Kořínková et al., 2020; Ruze et al., 2023). Indeed, approved anti-obesity/antidiabetic drugs have also been evaluated in clinical trials for the treatment of NAFLD patients; these medications include glucagon-like peptide (GLP)-1 receptor agonists and the orlistat, a gastrointestinal lipase inhibitor. Interestingly the GLP-1 receptor (GLP1R) agonists liraglutide and semaglutide as well as the orlistat have shown beneficial effects on the two hits typical of NAFLD, the hepatic steatosis and the inflammatory process (for review see (Polyzos et al., 2022)). For instance, GLP1R agonists and orlistat reduce the production of proinflammatory adipokines, chemokines, and cytokines as well as their circulating levels (Domingo et al., 2024). Moreover, by unraveling the molecular mechanisms behind the antidiabetic and anti-obesity therapeutic effect of both GLP-1 agonists and orlistat, the researchers find that these medications can affect the autophagy flux, thus supporting that the evidence collected in the present review might represent a concrete perspective for future pharmacological interventions (Rowlands et al., 2018; Park and Lee, 2022; Domingo et al., 2024). Specifically, it has been shown (Fan et al., 2018) that, the antidiabetic effect of liraglutide is associated with an improvement of pancreatic defective autophagy obtained by the upregulation of ATG5 and LC3 expression in a mouse model of T2DM. In support of such a hypothesis, in another study (He et al., 2016) liraglutide was shown to improve hepatic steatosis associated with NAFLD, by inducing autophagy flux, and such effect was also associated with a decrease in body weight and decreased accumulation of TGs and cholesterol. This result is also supported by an in vitro experiment (performed in hepatocytes in which steatosis was induced by free fatty acids exposure) suggesting that liraglutide has a protective effect on hepatic steatosis which is mediated by the activation of autophagy flux particularly throughout the AMPK/mTOR pathway (Liao et al., 2024). The same conclusion has been achieved in another set of experiments where the authors demonstrated that liraglutide alleviates NAFLD by restoring autophagy via improving lysosomal function (Fang et al., 2020). Also, sitagliptin, a dipeptidyl-peptidase 4 inhibitor, has been reported to exert more biological properties beyond its antidiabetic effect; in particular, it has been shown to ameliorate the development of liver steatosis by inhibiting inflammatory responses and by activating autophagy via AMPK/mTOR pathway (Zheng et al., 2018). Although experiences in a different context, also the incretin-mimetic semaglutide and orlistat have been shown to affect the autophagy flux (Peng et al., 2018; Chang et al., 2020; Liu et al., 2022), thus further corroborating the idea that the therapeutic effect of such medicaments might be at least in part due to the modulation of autophagy.

Interestingly also the anorexigenic compound, oleoylethanolamide (OEA), a high-affinity agonist of the peroxisome proliferator-activated receptor alpha (PPAR-alpha), highly studied in the last 2 decades for its beneficial effect on food intake, lipid metabolism, and body weight (Romano et al., 2015; 2017; 2020b) has been suggested, although indirectly, to affect autophagy. Therefore, it has been demonstrated that OEA possesses a beneficial effect in vascular calcification induced by metabolic dysfunctions via inhibiting ferroptosis, a specific type of cell death dependent on autophagy; such effect was strictly dependent on the activation of PPAR-alpha (Chen et al., 2023). This latter result acquires considerable importance if we consider that the PPAR-alpha agonists i) GW7647 reverse feeding-induced autophagy suppression (Lee et al., 2014) and ii) fenofibrate, ameliorates HFD-induced kidney injury in diabetic kidney disease via autophagy activation (Sohn et al., 2017), thus supporting the role of PPAR-alpha, already known to regulate fatty acid metabolism, in activating autophagy. Also, the antidiabetic inhibitors of the sodium-glucose cotransporter 2 (SGLT2) have been demonstrated to augment autophagy in preclinical experiments performed in animals and cell cultures. In particular, SGLT2 inhibitors produce beneficial effects on the progression of both cardiomyopathy and nephropathy associated with diabetes by enhancing the autophagic flux in different tissues and organelles including the mitochondria. The enhancement of autophagy induced by SGLT2 inhibitors is accompanied by a reduction in oxidative stress, restoration of functional mitochondria, and a decrease in proinflammatory mediators thus contributing to the maintenance of physiological organ morphology and functions [for review see (Packer, 2022)]. Additionally, the research is also concentrated on the study of direct (Park and Lee, 2022) autophagy enhancers, including berberine, imatinib, and rapamycin in the potential treatment of metabolic diseases. In this regard, Panigrahi and Mohanty (Panigrahi and Mohanty, 2023) recently reported the results obtained from a randomized controlled trial (CTRI/2021/12/038751) on the effect of berberine in prediabetic patients. Particularly, the author showed that after 12 weeks of daily oral berberine (HIMABERB^®) treatment, the glycemic markers were significantly improved thus supporting the potentiality of a direct enhancement of autophagy in the delaying of diabetes progression.

Although the present review is focused on the pharmacological modulation of autophagy to dampen inflammation in metabolic diseases, it is worth mentioning that also non-pharmacological approaches including diet management, fasting, and exercise have been studied for their ability to affect autophagy in such a context. For instance, it has been demonstrated that caloric restriction and physical activity serve as potent mechanisms for upregulating autophagy (van Niekerk et al., 2018), resulting in being dampened by excessive nutrition and a sedentary lifestyle. In particular, fasting can enhance mitophagy, by facilitating the removal of damaged mitochondria, and consequently by reducing ROS production (van Niekerk et al., 2018). Moreover, it has also been shown that exercise triggers autophagy in multiple organs that play a key role in metabolic regulation, including muscle, liver, pancreas, and adipose tissue (He et al., 2012), thus highlighting the importance of physical activity in a daily routine to improve health. Further research, also in nutrition, has studied different nutrient approaches as activators of autophagy. For instance, a link between the ketogenic diet and autophagy activation has been demonstrated in a preclinical study where the mice were fed a ketogenic diet for 4 weeks, which induced an enhancement of autophagy in hepatocytes (for review see (Kocot and Wróblewska, 2022)). Finally, several reports elucidate autophagy-related signal pathways of functional foods, including some bioactive components such as resveratrol, epigallocatechin-3-gallate, and curcumin (for review see (Xie et al., 2019)).

Further discussion on such non-pharmacological interventions is out of the aim of the present review although they seem promising in supporting traditional pharmacological treatments for diseases related to dysregulated autophagy including obesity and metabolic disorders.

The studies collected in the present review provide evidence of the sophisticated affair between inflammation and autophagy in modulating biological events regulating energy homeostasis and metabolism. The most prominent conclusion mainly coming from the preclinical studies (summarized in Table 1) is that autophagy exerts a protective function by contributing to balance inflammation occurring in obesity and metabolic diseases; on the contrary, an altered autophagy might lead to maladaptive metabolic and inflammatory responses thus exacerbating the severity of the disease.

Although the majority of the studies reported in the present review have been performed in laboratory animals it is reasonable to hypothesize their future clinical practice application; this latter concept is strongly supported by the observation that drugs already on the market, used for the control of obesity and other metabolic disorders, are also able to facilitate autophagy processes by dampening inflammation. This evidence strongly contributes to the idea that targeting autophagy and inflammation might represent a druggable system for the management of such diseases.

However, the complex nature of obesity and metabolic disorders might represent a limit of the studies reported here; indeed, although many pharmacological treatments, producing positive metabolic effects, are also able to modulate autophagic flux and inflammation, it is not clear if the final beneficial effect might occur only by their mechanism of action, rather than because of additionally involved pathways. In addition, most of the drugs targeting autophagy and inflammation do not directly modulate such processes but rather affect upstream involved pathways, thus suggesting a more intricate view that deserves further exploration. This concept should foster future studies aimed at a better understanding of whether the beneficial effect accounts because of the selective pharmacological modulation of one of the two processes (autophagy or inflammation) which in turn regulate the other or if they are the result of a concerted action of the same drug on the two systems at the same time.

These studies might help to better identify the molecular mechanism of action of drugs already on the market and, might open the way for the development of novel pharmacological approaches for the treatment of obesity and metabolic diseases.