Targeting autophagy in obesity: from pathophysiology to management

Abstract

Obesity poses a severe threat to human health, including the increased prevalence of hypertension, insulin resistance, diabetes mellitus, cancer, inflammation, sleep apnoea and other chronic diseases. Current therapies focus mainly on suppressing caloric intake, but the efficacy of this approach remains poor. A better understanding of the pathophysiology of obesity will be essential for the management of obesity and its complications. Knowledge gained over the past three decades regarding the aetiological mechanisms underpinning obesity has provided a framework that emphasizes energy imbalance and neurohormonal dysregulation, which are tightly regulated by autophagy. Accordingly, there is an emerging interest in the role of autophagy, a conserved homeostatic process for cellular quality control through the disposal and recycling of cellular components, in the maintenance of cellular homeostasis and organ function by selectively ridding cells of potentially toxic proteins, lipids and organelles. Indeed, defects in autophagy homeostasis are implicated in metabolic disorders, including obesity, insulin resistance, diabetes mellitus and atherosclerosis. In this Review, the alterations in autophagy that occur in response to nutrient stress, and how these changes alter the course of obesogenesis and obesity-related complications, are discussed. The potential of pharmacological modulation of autophagy for the management of obesity is also addressed.

CD74 knockout protects against LPS‐induced myocardial contractile dysfunction through AMPK‐Skp2‐SUV39H1‐mediated demethylation of BCLB

“…This speculation (as depicted in Figure ) also received support from O 2 − production and mechanical findings in Figure , where activation of AMPK, autophagy and methylation blocked the CD74 knockout benefit against LPS‐induced cardiomyocyte anomalies. It was reported that oxidative stress induces autophagy through JNK‐, Akt‐ or AMPK‐mediated pathways (Ren et al, ; Zhang, Sowers, & Ren, ). Our findings suggested a likely role for the Akt‐AMPK‐mTOR signalling cascade in bridging oxidative stress and autophagy in endotoxemia.…”

Obesity and ageing: Two sides of the same coin

“…Mitophagy is an indispensable quality control mechanism constantly removing damaged and dysfunctional mitochondria to maintain optimal function of different tissues in the body. Impaired mitophagy in different tissues has been associated with frailty, cardiovascular, neurodegenerative, and metabolic diseases in obesity and ageing . Recently, studies showed that impaired mitophagy is linked to macrophage lineage, which is crucial to age‐related changes and chronic inflammation in obesity .…”

“…Impaired mitophagy in different tissues has been associated with frailty, cardiovascular, neurodegenerative, and metabolic diseases in obesity and ageing. 63,64 Recently, studies showed that impaired mitophagy is linked to macrophage lineage, which is crucial to age-related changes and chronic inflammation in obesity. 65 Accumulation of damaged mitochondria in macrophages due to insufficient mitophagy activates excessive secretion of IL-1β, which enhances macrophage death and compromises macrophage-mediated immunity, tissue repair, and healing.…”

The physiological roles of autophagy in the mammalian life cycle

“…The functions of autophagy are widespread and alteration of normal autophagy leads to a plethora of diseases, which have been reviewed elsewhere (Mizushima & Komatsu, 2011;Kim & Lee, 2014). Dysfunction of autophagy in different tissues results in distinct a range of diseases (Saha et al, 2018;Xie & Zhou, 2018), including neurodegeneration (Xie & Zhou, 2018), cardiac diseases (Lavandero et al, 2015), immune diseases (Pengo et al, 2013;Netea-Maier et al, 2016;Hua et al, 2018), obesity (Zhang, Sowers & Ren, 2018), tumorigenesis (Kimmelman & White, 2017),renal diseases (De Rechter et al, 2016) and oral diseases (Tan, Zhang & Zhou, 2017), among others.…”