The PI3K/AKT pathway in obesity and type 2 diabetes

“AKT-mediated mTORC1 activation regulates a number of downstream effectors proteins through phosphorylation, including the well-characterized effectors p70 ribosomal S6 protein kinase-1 (S6K1) and eukaryotic translation initiation factor-4E (eIF4E)binding protein-1 (4E-BP1), to increase protein synthesis [43, 44].”

“First, phosphorylation of the threonine 308 (AKT1) in the kinase domain by phosphoinositide-dependent protein kinase 1 (PDK1) initiates the activation process [19], subsequent phosphorylation at serine 473 (AKT1) in the carboxy-terminal regulatory domain through mTOR complex 2 (mTORC2)[17, 20], which is activated by a…”

“AKT regulates two processes by glycolysis Glucose 6-phosphate and glycogen synthase kinase 3 (GSK3) to produce cellular energy via glycolysis and promotes glycogen production by inhibiting [30].”

“In obese subjects, excess levels of circulating FFAs, which are caused by a blunted response of adipose tissues, impairs the function of β cells [150].”

“In the feeding state, SREBP-1c is regulated by four pathways: activated AKT stimulates liver X receptor (LXR), which is require for SREBP-1c transcription [64]; activated AKT stimulates mTORC1 to activate SREBP-1c transcription, and mTORC1 also inhibits Lipin-1, which decreases the half-life of nuclear SREBP-1c [65, 6…”

“Similar phosphorylation events are observed at corresponding residues in AKT2 (T309 and S474) and AKT3 (T305 and S472) [22].”

“In the presence of persistent excess energy availability, leptin signalling activates other pathways, such as STAT3 or SH2-containing tyrosine phosphatase, to predominantly regulate food intake in POMC neurons [90, 113, 119].”

“First, phosphorylation of the threonine 308 (AKT1) in the kinase domain by phosphoinositide-dependent protein kinase 1 (PDK1) initiates the activation process [19], subsequent phosphorylation at serine 473 (AKT1) in the carboxy-terminal regulatory domain through mTOR complex 2 (mTORC2)[17, 20], which is activated by a…”

“Chronic metabolic inflammation and endoplasmic reticulum (ER) stress also impair hepatic insulin-AKT signalling and subsequently causes insulin resistance [106, 107].”

“The prevalence of obesity has grown at an alarming rate although specific public health policies and treatment efforts have been developed to resist the obesity epidemic [1], potentially leading to increased numbers of patients affected by complications of obesity, such as the most devastating type 2 diabetes mellitus…”

“Unfortunately, these treatments currently cannot ensure long-term glycaemic control or reverse the progress [4].”

“In the feeding state, SREBP-1c is regulated by four pathways: activated AKT stimulates liver X receptor (LXR), which is require for SREBP-1c transcription [64]; activated AKT stimulates mTORC1 to activate SREBP-1c transcription, and mTORC1 also inhibits Lipin-1, which decreases the half-life of nuclear SREBP-1c [65, 6…”

“The substrate SREBP, which regulates fatty acid synthase and cholesterol-related genes [18, 61], and FOXO1, which regulates lipolysis by controlling the expression of adipose triglyceride lipase (ATGL) [62], are primary substrates for AKT-mediated lipid metabolism [63].”

“Meanwhile, RTKs and GPCRs also activates Ras to subsequently activates PI3K [14].”

“[138], activation of S6K1, a downstream effector of mTORC1, in hypothalamic neurons leads to hepatic insulin resistance because it decreases the stimulation of IRS-1 and AKT.”

“Activated Class I PI3K phosphorylates the substrate phosphatidylinositol 4,5-biphosphate (PIP2) to form phosphatidylinositol 3,4,5-triphosphate (PIP3) on intracellular membranes, subsequently recruiting signalling proteins, including AKT[15].”

“PI3Ks are a family of lipid kinases that phosphorylate phosphatidylinositol, which is a component of eukaryotic cell membranes [10].”

“In the feeding state, SREBP-1c is regulated by four pathways: activated AKT stimulates liver X receptor (LXR), which is require for SREBP-1c transcription [64]; activated AKT stimulates mTORC1 to activate SREBP-1c transcription, and mTORC1 also inhibits Lipin-1, which decreases the half-life of nuclear SREBP-1c [65, 6…”

“mTOR, a well-known phosphorylation target of AKT, specifically binds to Rheb GTPase with GTPase-activating protein (GAP) activity, which directly activates mTORC1[121].”

“Ceramides disturb insulin signalling by AKT, leading to reduction of glucose utilization [54].”

“β cell-specific knockout of IRS2 or the IR, which disrupts of insulin signalling in pancreatic β cells, reduces the pancreatic insulin content, β cell mass and glucose-stimulated insulin secretion, followed by the development of a phenotype similar to T2DM [140, 141].”

“AKT directly phosphorylates AS160, inducing GLUT4 translocation, which translocated to the plasma membrane from storage vesicles and transports glucose in skeletal muscle following stimulation of insulin and AKT [38, 39].”

“In the chronically obesity, the prevalence of diabetes significantly increased, which is four times higher than the general population [5].”

“Protein phosphatase 2A (PP2A) [23] and PH domain leucine-rich repeat protein phosphatases (PHLPP1 and PHLPP2) [24] dephosphorylate AKT T308 and S473, respectively, leading to AKT inactivation.”

“caemia, along with various comorbidities, such as cardiovascular disease, obesity, microangiopathy and renal failure [3].”

“PI3K, Phosphoinositide 3-kinase; AKT, protein kinase B; T2DM, type 2 diabetes mellitus; RTKs, receptor tyrosine kinases; GPCR, G-protein-coupled receptors; PIP2, phosphatidylinositol 4,5-biphosphate; PIP3, phosphatidylinositol 3,4,5-triphosphate; PTEN, Phosphatase and tensin homologue; PDK1, phosphoinositide-dependent…”

“In the feeding state, SREBP-1c is regulated by four pathways: activated AKT stimulates liver X receptor (LXR), which is require for SREBP-1c transcription [64]; activated AKT stimulates mTORC1 to activate SREBP-1c transcription, and mTORC1 also inhibits Lipin-1, which decreases the half-life of nuclear SREBP-1c [65, 6…”

“Phosphoinositide 3-kinase (PI3K) was discovered in 1985 and identified as a previously unknown phosphoinositide kinase [7, 8].”

“Another way to regulate HGP is PI3K-stimulated generation of PIP3 in AgRP neurons, which activates K (ATP) channels, decreasing G6PC expression in the liver [91].”

“AKT suppresses the expression of INSIG2A, a liver-specific transcript encoding the SREBP-1c inhibitor INSIG2, through an mTORC1-independent pathway [98].”

“Most of the extracellular glucose is produced in the kidneys and liver, and only the liver acutely responds to insulin by reducing glucose levels [81].”

“second, brain insulin action is attenuated or even diminished in response to both endogenous and exogenous insulin stimulation [133], which impairs hypothalamic AKT activation due to ER stress and the activation of inflammatory pathways [134].”

“On the other hand, FoxO1 induces the expression of phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase gene (G6PC), subsequently increases gluconeogenesis [33].”

“First, insulin action in the hypothalamus through K (ATP) channels decrease expression of G6PC and hepatic glucose production (HGP) in liver [89, 90].”

“Those effectors share a common minimal sequence motif, Arg-Xaa-Arg-Yaa-Zaa-Ser-Hyd [28].”

“PI3K, Phosphoinositide 3-kinase; AKT, protein kinase B; T2DM, type 2 diabetes mellitus; RTKs, receptor tyrosine kinases; GPCR, G-protein-coupled receptors; PIP2, phosphatidylinositol 4,5-biphosphate; PIP3, phosphatidylinositol 3,4,5-triphosphate; PTEN, Phosphatase and tensin homologue; PDK1, phosphoinositide-dependent…”

“In the presence of adipose hypertrophy, insulin resistance also occurs because of the expansion of adipose tissues exceeds their storage capacity [45, 78, 79].”

“However, insulin has consistently been shown to play an important role in pancreatic cells [139], mainly through PI3K/AKT”

“Activation of the PI3K/AKT pathway promotes insulin secretion form pancreatic β cells [142, 143].”

“Excessive lipid production and impaired disposal may promote the development of insulin resistance and diabetes in the skeletal muscle [47, 48].”

“PI3K, Phosphoinositide 3-kinase; AKT, protein kinase B; T2DM, type 2 diabetes mellitus; RTKs, receptor tyrosine kinases; GPCR, G-protein-coupled receptors; PIP2, phosphatidylinositol 4,5-biphosphate; PIP3, phosphatidylinositol 3,4,5-triphosphate; PTEN, Phosphatase and tensin homologue; PDK1, phosphoinositide-dependent…”

“FoxO1 and peroxisome proliferator-activated receptor-coactivator 1α (PGC1α) coordinately regulate gene expression to increase gluconeogenesis and fatty acid oxidation [32].”

“In previous studies, insulin suppressed PEPCK and G6PC expression, which are known to increase hepatic gluconeogenesis by activating the PI3K/AKT pathway [84-86].”

“In a subsequent study, leptin and insulin were shown to coordinately regulate FoxO1 activity, increasing the expression of NPY and AgRP and suppressing POMC expression [115, 116].”

“Three pathways may mediate cell-nonautonomous effects on hepatic glucose metabolism [88].”

“AKT1 expresses ubiquitously, AKT2 mainly expresses in insulin-sensitive tissues, such as skeletal muscle, adipose tissues and liver, and AKT3 expresses in the testes and brain [9, 18].”

“In the hypothalamic arcuate nucleus (ARC), anorexigenic proopiomelanocortin (POMC) and orexigenic AgRP coordinately regulate food intake and energy expenditure, as well as peripheral tissue glucose homeostasis and energy partitioning through insulin, leptin and nutrients [111].”

“Approximately 90% of insulin-stimulated glucose utilization occurs in skeletal muscle and plays an important role in regulating glucose metabolism and energy homeostasis [36].”

“In early studies, insulin resistance was thought to be accompanied by excessive intramyocellular lipid (IMCL) levels [49], and improved insulin sensitivity observed in subjects with T2DM by reduced IMCL levels [50].”

“In the presence of adipose hypertrophy, insulin resistance also occurs because of the expansion of adipose tissues exceeds their storage capacity [45, 78, 79].”

“First, phosphorylation of the threonine 308 (AKT1) in the kinase domain by phosphoinositide-dependent protein kinase 1 (PDK1) initiates the activation process [19], subsequent phosphorylation at serine 473 (AKT1) in the carboxy-terminal regulatory domain through mTOR complex 2 (mTORC2)[17, 20], which is activated by a…”

“In the presence of persistent excess energy availability, leptin signalling activates other pathways, such as STAT3 or SH2-containing tyrosine phosphatase, to predominantly regulate food intake in POMC neurons [90, 113, 119].”

“Additionally, those mice still maintained the normal postprandial state, even in the absence of canonical liver insulin signalling [85, 87].”

“The selective inactivation of IR in AgRP neurons in mice results in an inability to suppress HGP whereas only a deficiency in both leptin and IRs in POMC neurons resulted in systemic insulin resistance [45, 129].”

“Phosphoinositide 3-kinase (PI3K) was discovered in 1985 and identified as a previously unknown phosphoinositide kinase [7, 8].”

“AKT regulates lipid metabolism through sterol regulatory element-binding proteins (SREBP), which increases cholesterol and fatty acid accumulation, including SREBP-1c, SREBP-1a, and SREBP-2[18, 34].”

“In the presence of persistent excess energy availability, leptin signalling activates other pathways, such as STAT3 or SH2-containing tyrosine phosphatase, to predominantly regulate food intake in POMC neurons [90, 113, 119].”

“Insulin signalling is blocked during insulin resistance in the brain due to increased protein kinase C (PKC) activity, ER stress and inflammation [134, 135], which blocks the ability of PI3K to generate PIP3.”

“In previous studies, insulin suppressed PEPCK and G6PC expression, which are known to increase hepatic gluconeogenesis by activating the PI3K/AKT pathway [84-86].”

“However, mTOR1 signalling is required for glucose homeostasis in the hypothalamus [126, 127].”

“First, phosphorylation of the threonine 308 (AKT1) in the kinase domain by phosphoinositide-dependent protein kinase 1 (PDK1) initiates the activation process [19], subsequent phosphorylation at serine 473 (AKT1) in the carboxy-terminal regulatory domain through mTOR complex 2 (mTORC2)[17, 20], which is activated by a…”

“AKT regulates lipid metabolism through sterol regulatory element-binding proteins (SREBP), which increases cholesterol and fatty acid accumulation, including SREBP-1c, SREBP-1a, and SREBP-2[18, 34].”

“In the feeding state, SREBP-1c is regulated by four pathways: activated AKT stimulates liver X receptor (LXR), which is require for SREBP-1c transcription [64]; activated AKT stimulates mTORC1 to activate SREBP-1c transcription, and mTORC1 also inhibits Lipin-1, which decreases the half-life of nuclear SREBP-1c [65, 6…”

“Leptin is the most important hormone reported to date that regulates food intake and energy balance [110].”

“In the feeding state, SREBP-1c is regulated by four pathways: activated AKT stimulates liver X receptor (LXR), which is require for SREBP-1c transcription [64]; activated AKT stimulates mTORC1 to activate SREBP-1c transcription, and mTORC1 also inhibits Lipin-1, which decreases the half-life of nuclear SREBP-1c [65, 6…”

“MCF7-tet OFF Sesn2F cells Sestrins (Sesn1/2/3) through activation of AMPK and mTORC2, which is necessary for activation of AKT Regulate both glucose and lipid metabolism [164, 165]”

“Pancreatic beta-cell glial cell line-derived neurotrophic factor (GDNF) Activates phosphorylation of AKT improves glucose tolerance and β cell mass [157, 158]”

“AKT directly inhibits FoxO1, reducing glucose levels [31], FoxO1”

“increases glycogen synthesis and the synthesis of fatty acids for storage and subsequent utilization by other tissues [82, 83].”

“Excessive fatty acid oxidation in the mitochondria via the tricarboxylic acid (TCA) cycle and the electron transport chain (ETC) increases the production of fatty acid metabolites and reactive oxygen species (ROS), subsequently activated intracellular stress kinases to inhibit IRS-1 and possibly exerting effects on in…”

“Chronic metabolic inflammation and endoplasmic reticulum (ER) stress also impair hepatic insulin-AKT signalling and subsequently causes insulin resistance [106, 107].”

“The substrate SREBP, which regulates fatty acid synthase and cholesterol-related genes [18, 61], and FOXO1, which regulates lipolysis by controlling the expression of adipose triglyceride lipase (ATGL) [62], are primary substrates for AKT-mediated lipid metabolism [63].”

“Although several studies have reported an absolute requirement for PI3K in AKT activation, AKT activation has also been suggested to be mediated by a PI3K-independent mechanism [27].”

“Leptin requires intact PI3K signalling to promote hypothalamic expression of POMC genes and inhibit expression of the NPY and AgRP genes [113, 114].”

“In contrast, overexpression of a kinase dead mutant in β cells, which reduced AKT activity by 80%, results in a lack of insulin secretion [145].”

“In the fed state, PI3K/AKT inhibits protein kinase A (PKA) and thus suppresses lipolysis.”

“However, this process triggers the ectopic accumulation of lipids and subsequently causes lipotoxicity and insulin resistance [75].”

“In normal physiology, feeding is able to activate synthesis of SREBP-1c via insulin-dependent pathway (mTORC1) or insulin-independent pathway (carbohydrate response element binding protein (ChREBP)) [59, 60].”

“MCF7-tet OFF Sesn2F cells Sestrins (Sesn1/2/3) through activation of AMPK and mTORC2, which is necessary for activation of AKT Regulate both glucose and lipid metabolism [164, 165]”

“In normal physiology, feeding is able to activate synthesis of SREBP-1c via insulin-dependent pathway (mTORC1) or insulin-independent pathway (carbohydrate response element binding protein (ChREBP)) [59, 60].”

“RTKs recruit class I PI3Ks to the plasma membrane, which relieves the inactivation function of p85 and p110 to activate the protein [12, 13].”

“Excessive fatty acid oxidation in the mitochondria via the tricarboxylic acid (TCA) cycle and the electron transport chain (ETC) increases the production of fatty acid metabolites and reactive oxygen species (ROS), subsequently activated intracellular stress kinases to inhibit IRS-1 and possibly exerting effects on in…”

“Previous research has found knockout or knockdown of AKT or IRS adaptor proteins obviously reduce insulin-induced glucose uptake, whereas overexpression of AKT increases glucose uptake [37].”

“Recently, Gpr17, the target of FoxO1, was shown to regulate feeding and sensitivity through insulin and leptin in AgRP neurons [117, 118].”

“As shown in a previous study, acute activation of mTOR1 promotes the ability of hypothalamic neural circuits to sense the nutritional milieu and regulate feeding [122, 123].”

“Both obesity and T2DM are associated with insulin resistance [6].”

“The role of FoxO1 in liver lipid metabolism is less well studied; some studies have shown that FoxO1 is directly associated with insulin-promoted expression of fat genes in the liver, whereas others have reported a permissive role for FoxO1 in these processes [100-102].”

“As shown in a previous study, acute activation of mTOR1 promotes the ability of hypothalamic neural circuits to sense the nutritional milieu and regulate feeding [122, 123].”

“Leptin and insulin-mediate PI3K/AKT signalling is impaired in the brains of obese subjects with insulin resistance [132].”

“including protecting tissues and organs from cold and hot, thermogenesis and the production of various hormones/cytokines that are collectively referred to as cytokines [56, 57].”

“Recently, endomembranes that contain PIP3 and PIP2 have also been shown to directly contribute to AKT activation [25, 26].”

“Additionally, those mice still maintained the normal postprandial state, even in the absence of canonical liver insulin signalling [85, 87].”

“Excessive lipid production and impaired disposal may promote the development of insulin resistance and diabetes in the skeletal muscle [47, 48].”

“In early studies, insulin resistance was thought to be accompanied by excessive intramyocellular lipid (IMCL) levels [49], and improved insulin sensitivity observed in subjects with T2DM by reduced IMCL levels [50].”

“The role of FoxO1 in liver lipid metabolism is less well studied; some studies have shown that FoxO1 is directly associated with insulin-promoted expression of fat genes in the liver, whereas others have reported a permissive role for FoxO1 in these processes [100-102].”

“In the presence of insulin resistance, the level of free fatty acids increases in the body resulting in the accumulation of intramyocellular lipids, such as DAG and ceramides [52].”

“In the feeding state, SREBP-1c is regulated by four pathways: activated AKT stimulates liver X receptor (LXR), which is require for SREBP-1c transcription [64]; activated AKT stimulates mTORC1 to activate SREBP-1c transcription, and mTORC1 also inhibits Lipin-1, which decreases the half-life of nuclear SREBP-1c [65, 6…”

“And recent study finds Irs2-knockout mice develop ‘selective insulin resistance’, whereas mice lacking in Irs1, or both Irs1 and Irs2, develop ‘total insulin resistance’, which indicates the IRS 1/2 are the cause of insulin selective resistance [109]; in the second, hepatic insulin signalling remains intact but the ce…”

“However, in the absence of AKT2, the activation of mTORC1 and SREBP-1c is not sufficient to drive postprandial lipid generation [99].”

“In a subsequent study, leptin and insulin were shown to coordinately regulate FoxO1 activity, increasing the expression of NPY and AgRP and suppressing POMC expression [115, 116].”

“Meanwhile, excessive oxidation of FFAs increases the hepatic acetyl-CoA content and thus activates pyruvate carboxylase, which is required for gluconeogenesis [45], and increases DAG levels, which impair PI3K/AKT pathway and exacerbate insulin resistance [48, 105].”

“AKT directly phosphorylates AS160, inducing GLUT4 translocation, which translocated to the plasma membrane from storage vesicles and transports glucose in skeletal muscle following stimulation of insulin and AKT [38, 39].”

“Class I PI3K is a heterodimer and is divided into class IA and class IB, according to differences in the molecular structure [11].”

“However, mTOR1 signalling is required for glucose homeostasis in the hypothalamus [126, 127].”

“PIP2 is synthesized by class II PI3Ks using PIP as substrate [16].”

“Recently, Another ligand, glucagon-like peptide (GLP-2), it was recently shown to play a key role in the control of HGP through the PI3K/AKT pathway[131], suggesting that in addition to insulin and leptin, GLP-2 also regulates HGP through PI3K/AKT signalling.”

“The pancreas is mainly composed of four types of cells, of which pancreatic β cells are vitally important in maintaining glucose homeostasis by producing and secreting insulin in response to the blood glucose concentration [58].”

“There are two reasons for this: first, the transport of insulin through the blood brain barrier is impaired in obese subjects [45].”

“At this point, the pharmacological inhibition of PI3K is an effective and safe anti-obesity and anti-cancer intervention that can reverse the negative effects of human diseases [152].”

“However, further studies should be carried on because the action of insulin in brain may not common in all species [92, 93].”

“Excessive fatty acid oxidation in the mitochondria via the tricarboxylic acid (TCA) cycle and the electron transport chain (ETC) increases the production of fatty acid metabolites and reactive oxygen species (ROS), subsequently activated intracellular stress kinases to inhibit IRS-1 and possibly exerting effects on in…”

“AKT has been reported to modulate the mTORC1-S6K1 pathway to regulate SREBP-1c expression in the liver [97].”

“second, brain insulin action is attenuated or even diminished in response to both endogenous and exogenous insulin stimulation [133], which impairs hypothalamic AKT activation due to ER stress and the activation of inflammatory pathways [134].”

“[161] C57BL/6 mice HepG2 cell glycerol kinase (Gyk) Decreases the expression of FoxO1 reduced expression of G6Pase and PEPCK [162] C57BL/6 mice NPC1L1 Regulates the AKT-FOXO1-PEPCK/G6Pase pathway reduced expression of G6Pase and PEPCK [163] MCF7-tet OFF Sesn2F cells Sestrins (Sesn1/2/3) through activation of AMPK and…”

“β cell-specific knockout of IRS2 or the IR, which disrupts of insulin signalling in pancreatic β cells, reduces the pancreatic insulin content, β cell mass and glucose-stimulated insulin secretion, followed by the development of a phenotype similar to T2DM [140, 141].”

“And the direct target of AKT is a substrate of 160 kDa (AS160), also known as TBC1D1 [29].”

“In early studies, insulin resistance was thought to be accompanied by excessive intramyocellular lipid (IMCL) levels [49], and improved insulin sensitivity observed in subjects with T2DM by reduced IMCL levels [50].”

“How does insulin resistance occur in adipose tissues? The synthesis and secretion of adiponectin, tumour necrosis factor-α (TNF-α) and interleukin 6 (IL-6), which enhance lipolysis by reducing perilipin and fat-specific protein 27 levels [76].”

“In the feeding state, SREBP-1c is regulated by four pathways: activated AKT stimulates liver X receptor (LXR), which is require for SREBP-1c transcription [64]; activated AKT stimulates mTORC1 to activate SREBP-1c transcription, and mTORC1 also inhibits Lipin-1, which decreases the half-life of nuclear SREBP-1c [65, 6…”

“The role of FoxO1 in liver lipid metabolism is less well studied; some studies have shown that FoxO1 is directly associated with insulin-promoted expression of fat genes in the liver, whereas others have reported a permissive role for FoxO1 in these processes [100-102].”

“One way to regulate HGP is that S6K1, a downstream molecule of mTOR1, regulates HGP, modulates neuronal excitability and peripheral lipid metabolism in POMC neurons, regulates the insulin sensitivity of skeletal muscle via AgRP neurons [128].”

“Recently, endomembranes that contain PIP3 and PIP2 have also been shown to directly contribute to AKT activation [25, 26].”

“In response to insulin resistance in the brain, overexpression of FoxO1 in POMC neurons leads to obesity and hyperphagia [136].”

“In skeletal muscle, insulin stimulates protein synthesis and accelerates mRNA translation by regulating the initiation steps of protein translation [42].”

“promotes peripheral insulin resistance [156]”

“Third, insulin functions through the AKT pathway suppress α-cell glucagon secretion in the brain, which reducing HGP levels in the liver [92, 95, 96].”

“For example, specifically knockdown of GLUT4 in adipose tissues resulted in insulin resistance in skeletal muscle and liver instead of adipose tissues [74].”

“AKT-mediated mTORC1 activation regulates a number of downstream effectors proteins through phosphorylation, including the well-characterized effectors p70 ribosomal S6 protein kinase-1 (S6K1) and eukaryotic translation initiation factor-4E (eIF4E)binding protein-1 (4E-BP1), to increase protein synthesis [43, 44].”

“AKT-independent, PI3K-dependent pathway also regulates adipocyte lipolysis by directly regulating PKA [72], AKT regulate FoxO1 through three pathway: reducing the expression of the rate-limiting lipolytic enzyme (ATGL), which is responsible for triacylglycerol hydrolase activity (ATGL) [62]; reducing the expression of…”

“Third, insulin functions through the AKT pathway suppress α-cell glucagon secretion in the brain, which reducing HGP levels in the liver [92, 95, 96].”

“The increased in subjects with obesity-induced inflammation, aggravating insulin resistance [77].”

“According to a recent study, mTOR1 is dispensable for the regulation of feeding behaviour and energy metabolism [124], and chronic activation of mTOR1 interferes with the hypothalamic neurons that regulate feeding and energy balance [125].”

“In addition, the PI3K/AKT pathway prevents lipotoxicity in pancreatic β cells by inhibiting FoxO1, which is abundantly expressed in pancreatic β cells and promotes FFA-induced β cell apoptosis [146, 147].”

“RTKs recruit class I PI3Ks to the plasma membrane, which relieves the inactivation function of p85 and p110 to activate the protein [12, 13].”

“Akt1 is ubiquitously expressed, whereas Akt2 is mainly expressed in insulin-sensitive tissues, such as AT, liver and skeletal muscle, and Akt3 is expressed in the brain and the testes [25].”