Autophagy in Adipocyte Browning: Emerging Drug Target for Intervention in Obesity

Abstract

Autophagy, lipophagy, and mitophagy are considered to be the major recycling processes for protein aggregates, excess fat, and damaged mitochondria in adipose tissues in response to nutrient status-associated stress, oxidative stress, and genotoxic stress in the human body. Obesity with increased body weight is often associated with white adipose tissue (WAT) hypertrophy and hyperplasia and/or beige/brown adipose tissue atrophy and aplasia, which significantly contribute to the imbalance in lipid metabolism, adipocytokine secretion, free fatty acid release, and mitochondria function. In recent studies, hyperactive autophagy in WAT was observed in obese and diabetic patients, and inhibition of adipose autophagy through targeted deletion of autophagy genes in mice improved anti-obesity phenotypes. In addition, active mitochondria clearance through activation of autophagy was required for beige/brown fat whitening – that is, conversion to white fat. However, inhibition of autophagy seemed detrimental in hypermetabolic conditions such as hepatic steatosis, atherosclerosis, thermal injury, sepsis, and cachexia through an increase in free fatty acid and glycerol release from WAT. The emerging concept of white fat browning–conversion to beige/brown fat–has been controversial in its anti-obesity effect through facilitation of weight loss and improving metabolic health. Thus, proper regulation of autophagy activity fit to an individual metabolic profile is necessary to ensure balance in adipose tissue metabolism and function, and to further prevent metabolic disorders such as obesity and diabetes. In this review, we summarize the effect of autophagy in adipose tissue browning in the context of obesity prevention and its potential as a promising target for the development of anti-obesity drugs.

TFEB deficiency attenuates mitochondrial degradation upon brown adipose tissue whitening at thermoneutrality

“…TFEB overexpression has recently been shown to drive browning of white adipose tissue in a PGC1A-dependent manner [ 63 ]. Additionally, autophagy is thought to be an important regulator of adipose tissue browning and adipocyte differentiation [ 54 , 55 , 76 ] and mitochondrial homeostasis in BAT during cold acclimation [ 77 ]. To investigate the role of BAT TFEB in the adaptation and response to cold stress, we monitored metabolic parameters of the TFEB BAT WT and KO mice that had previously been housed under standard conditions in response to different ambient temperatures ( Figure 4 A).…”

“…Targeting early steps of mitophagy, such as Parkin, has been shown to result in retained mitochondrial mass in brite/beige adipose tissue during whitening following the withdrawal of browning stimuli [ 47 ]. Therefore, the function of autophagy in regulating white adipose tissue browning or the maintenance of brite/beige adipocytes has been posited to represent a novel target to enhance thermogenic capacity [ 55 ]. In addition to regulating mitochondrial turnover, autophagy also affects adipocyte differentiation and adipogenesis in vivo and in vitro [ 54 , 96 , 98 ], but we did not find strong effects of TFEB deletion on adipocyte differentiation.…”

“…TFEB and TFE3 not only regulate the expression of lysosomal genes but also the autophagosomal machinery [ 51 ], thereby controlling mitochondrial degradation [ 52 ] and whole-body metabolism by affecting mitochondrial dynamics in the liver [ 53 ]. Autophagy has also been shown to directly influence the differentiation of adipocytes [ 54 , 55 ]. Interestingly, TFEB and TFE3 interact with the master regulators of mitochondrial biogenesis, PGC1-alpha and PPAR-gamma [ 56 , 57 ], regulating mitochondrial mass and exercise endurance in skeletal muscle [ 58 , 59 ].…”

Diphyllin Improves High-Fat Diet-Induced Obesity in Mice Through Brown and Beige Adipocytes

“…Autophagy is needed to convert beige adipocytes to WAT upon removal of b3-AR agonists or recovery from cold exposure, revealing that autophagy plays a negative role in beige adipocyte maintenance (63). It seems that a good anti-obesity strategy would be to inhibit autophagy, but due to inhibition of autophagy seeming detrimental in hypermetabolic conditions such as hepatic steatosis, atherosclerosis, thermal injury, sepsis, and cachexia through an increase in free fatty acid and glycerol release from WAT, the emerging concept of white fat browning-conversion to beige/ brown fat has been controversial in its anti-obesity effect through facilitation of weight loss and improvement in metabolic health (64). In summary, diphyllin improved brown and beige adipocyte differentiation and thermogenesis.…”

Sestrin2 Phosphorylation by ULK1 Induces Autophagic Degradation of Mitochondria Damaged by Copper-Induced Oxidative Stress

“…Autophagy, a highly conserved process among plants, eukaryotes, and metazoan, degrades and recycles damaged proteins and organelles and also unwanted cellular aggregates in response to stress conditions [ 16 ]. Proper autophagy is important for cellular homeostasis, as its deregulation is associated with diverse metabolic pathologies in both white and brown adipocytes [ 17 , 18 , 19 , 20 ]. Mitochondria-enriched metabolic tissue-specific loss of autophagy in mice and humans causes lipid accumulation, unbalanced cytokine secretion, inflammation, and metabolic dysfunction [ 21 , 22 ].…”