Mechanistic target of rapamycin mTOR a highly conserved
Mechanistic target of rapamycin (mTOR), a highly conserved serine-threonine protein kinase, is a key regulator of cell growth and metabolism. As discussed above, mTORC1 is a negative regulator of the preinitiation complex that modulates the initiation of autophagosome biogenesis. Pharmacological and genetic evidence has demonstrated that mTORC1 is required for adipogenesis and adipose maintenance in vitro. mTOR activation suppresses lipolysis, stimulates lipogenesis, and promotes fat storage. The phenotypes observed following mTOR activation in adipocytes are difficult to reconcile with the phenotypes of adipocyte-specific Atg5 or Atg7 knockout mice, because mTOR activation should lead to decreased autophagy. However, there are some distinctive differences here. Unlike adipocyte-specific Atg5 or Atg7 knockout mice, mTOR activation may not be able to completely eliminate autophagy. In addition, autophagy can also occur independently of mTOR. Therefore, whether autophagy is involved in mTOR-regulated adipocyte biology remains to be further investigated.
Autophagy and beige adipocyte remodeling As briefly mentioned above, beige adipocytes, also called browning of white fat, were recently identified as a distinct type of thermogenic fat that exerts anti-obesity effects by burning FA and angiotensin receptor blockers instead of storing lipids. Both beige adipocytes and the traditional brown adipocytes are competent for thermogenesis through the actions of UCP1 and share similar morphological characteristics, such as multilocular LDs and abundant mitochondria. Beige adipocytes are inducible and derived from white adipocytes in response to cold stress or pathways that elevate intracellular cAMP. Interestingly, the “browning of white” process is reversible, and beige adipocytes can return to white adipocytes by removing excess mitochondria, likely via selective autophagy of mitochondria (mitophagy). Indeed, a recent report provided strong evidence to support the concept that the autophagy pathway is crucial for mitochondrial clearance during the beige-white transition. Adipocyte-specific Atg5 or Atg12 knockout mice prevent the beige adipocyte loss after withdrawing external stimuli. These mice also maintain high thermogenic capacity and are protected against diet-induced obesity and insulin resistance. Selective mitophagy is mediated by the PTEN-induced putative kinase 1 (Pink1)-Parkin pathway, but it remains unclear whether Pink1 or Parkin plays a role in mitophagy during the beige-white transition.
Alcohol and adipocyte tissue atrophy Increasing evidence has revealed that the crosstalk between adipose tissue and liver is important in liver diseases, since adipose tissue is not only a lipid store but also a crucial endocrine organ that secretes various adipokines. Adiponectin, an adipokine exclusively secreted by adipose tissue and agonist of peroxisome proliferator-activated receptor gamma (PPAR-γ), a receptor crucial for maintaining adipose expansion and adiposity, improves lipid dysregulation and liver steatosis in mice. As discussed above, hepatic steatosis is a hallmark of ALD and indicative of early pathogenesis. Several mechanisms contribute to alcohol-induced steatosis, including increased lipid uptake and synthesis, decreased FA β-oxidation and very-low-density lipoprotein secretion, and altered humoral factor levels. Epidemiology studies have demonstrated that habitual moderate and heavy drinkers have lower body mass indexes, especially in males. It is generally agreed that alcohol exposure leads to adipose tissue atrophy. In contrast, aberrant body fat distribution and excessive adipose tissue accumulation may exacerbate ALD development, as abdominal height is positively associated with fibrosis score in patients with ALD. Abundant evidence from animal experiments also indicates that long-term alcohol intake induces adipose atrophy and disturbs lipid metabolism in adipose tissue, especially in WAT. Chronic alcohol intake (4 weeks) in rats decreased WAT and increased TG degradation and lipolysis. Chronic alcohol exposure (8 weeks) in mice reduced WAT, stimulated adipose tissue lipolysis, and inhibited adipose FA uptake. However, supplementation with rosiglitazone, a PPARγ agonist, normalized adipose gene expression and corrected lipid dyshomeostasis. In addition to increased lipolysis in adipocytes, chronic ethanol consumption in rats resulted in decreased expression of lipogenic enzymes, including PPAR-γ and CCAAT/enhancer-binding protein alpha, in epididymal WAT, suggesting that adipocyte tissue atrophy may also be due to decreased lipogenesis. Notably, visceral WAT with higher acetaldehyde dehydrogenase metabolism was more susceptible to ethanol treatment than subcutaneous WAT, and aldehyde treatment in vitro and ex vivo was sufficient to suppress lipogenic enzymes. This suggests that aldehyde, a product of alcohol metabolism, may inhibit lipogenesis and contribute to the lipodystrophy in adipose tissue.