BLDE University Journal of Health Sciences

REVIEW ARTICLE
Year
: 2021  |  Volume : 6  |  Issue : 1  |  Page : 7--21

Obesity and chronic leptin resistance foster insulin resistance: An analytical overview


Sananda Dey1, Nensina Murmu2, Mayukh Bose3, Shilpi Ghosh4, Biplab Giri1,  
1 Department of Physiology, University of Gour Banga, Malda; Experimental Medicine and Stem Cell Research Laboratory, Department of Physiology, West Bengal State University, Kolkata, India
2 Department of Physiology, University of Gour Banga, Malda, West Bengal, India
3 Experimental Medicine and Stem Cell Research Laboratory, Department of Physiology, West Bengal State University, Kolkata, West Bengal, India
4 Department of Biotechnology, University of North Bengal, Darjeeling, West Bengal, India

Correspondence Address:
Prof. Biplab Giri
Department of Physiology, University of Gour Banga, Malda - 732 103, West Bengal
India

Abstract

Leptin is secreted from adipose tissue, maintains energy balance in our body, and regulates appetite via arcuate nucleus of the hypothalamus. It binds with its receptor (LepR) to kick-start multiple reaction cascades such as Janus kinase 2/signal transducer and activator of transcription 3, suppressor of cytokine signaling-3, insulin receptor substrate 1, phosphatidyl inositol 3-kinase, and protein kinase B-Akt. Insulin increases the uptake of fatty acids and enhances cellular glucose uptake and utilization. Insulin's metabolic effects are mediated by a number of tissue-specific pathways, some of which crosstalk leptin-mediated signaling. Studies showed that leptin resistance is instigated due to the excess release of leptin from adipocytes. It causes a lack of sensitivity toward leptin, for which the body fails to attain satiety and results in more food intake which in turn induces more obesity and aggravates further leptin resistance. Emphasizing on obesity, this review directs toward a possibility of chronic leptin resistance being responsible for insulin resistance. The above statement has been elicited by delineating the point of convergence between insulin and leptin signaling pathways.



How to cite this article:
Dey S, Murmu N, Bose M, Ghosh S, Giri B. Obesity and chronic leptin resistance foster insulin resistance: An analytical overview.BLDE Univ J Health Sci 2021;6:7-21


How to cite this URL:
Dey S, Murmu N, Bose M, Ghosh S, Giri B. Obesity and chronic leptin resistance foster insulin resistance: An analytical overview. BLDE Univ J Health Sci [serial online] 2021 [cited 2021 Dec 5 ];6:7-21
Available from: https://www.bldeujournalhs.in/text.asp?2021/6/1/7/307611


Full Text



The modern day population has been subjected to a deskbound life and unhealthy food habits that include consumption of readily available, calorie dense, packaged, and processed foods. This happens due to excess dependencies on machines and technology in the working environment.[1] Recent studies have shown that obesity is a major problem in modern human society. More and more intake of refined carbohydrates negatively influences the metabolism and neural addiction mechanisms, which aids in weight gain. As the adipose tissue mass accumulates, satiety centers in the hypothalamus become resistant to leptin and insulin, which lead to increased calorie consumption. This also results in lipid accumulation in the liver and skeletal muscles at a larger content.[2] Besides this, irregular meals and snacking habits also disturb the natural circadian clock, thus disrupting energy homeostasis leading to serious metabolic disorders[3] and transforming healthy, lean subjects to obese individuals. Some of them show symptoms of type-2 diabetes and eventually start to suffer, while others remain asymptomatic but are prone to suffer from diabetes.[4] In some cases, obese people suffered from albuminuria, glomerulomegaly, and secondary focal glomerulosclerosis,[5] while many suffered from inflammation due to excess production of tumor necrosis factor-α (TNF-α) and interleukin (IL-6).[6] Coronary heart disease and high blood pressure are common problems associated with obesity,[7] which also occurs due to stress and sedentary lifestyle. Leptin is an adipocytokine which is secreted from lipocytes and regulates food intake by inhibiting neuropeptide-Y (NPY) in the arcuate nucleus of the hypothalamus. After it is released in the blood, it is transported to its site of action through the leptin carrier proteins. The amount of leptin circulating in the body is proportional to the amount of fat in an individual.[8] Research has revealed that an increased amount of leptin released in the blood renders it less effective in the brain for controlling hunger and food intake. It results in uncontrolled feeding, leading to greater food intake and fat storage.[9] Excessive release of leptin from fat cells due to obesity blunts the action of leptin and subsequently results in leptin resistance.

In this review, we have tried to find out and analyze the critical relationship between obesity, leptin resistance, and insulin resistance and the cross talk of their signaling pathways, responsible for the promotion of insulin resistance.

 Biology of Leptin and Leptin Receptor (Ob-R)



Adipose tissue secret multiple adipokines such as chemokines, cytokines, and hormones of which many are involved in energy balance. In obesity, the adipocyte plays an integral role in the development of obesity-induced inflammation via increasing secretion of various pro-inflammatory cytokines and chemokines.[10] Some of them, including monocyte chemotactic protein-1, TNF-α, IL-1, IL-6, and IL-8, have been accounted to endorse insulin resistance.[11],[12],[13],[14],[15] Leptin, a 167 amino acid polypeptide produced from the human leptin gene (Ob gene), was initially revealed through positional cloning of ob/ob mice, a mouse model for diabetes and obesity, originally developed at the Jackson Laboratories in 1949.[16] The ob/ob mouse has spontaneous mutations in the Lepob gene, also known as the Lep gene, from which the leptin is synthesized. As this gene is mutated at both the allelic positions on chromosome 6, these ob/ob mice are leptin-deficient and show characteristic morbid obesity.[16],[17] However, the administration of leptin to these leptin-deficient mice was seen to be effective in reducing hyperphagia with increased energy expenditure and sustained loss in weight.[18] Leptin is secreted mainly from the white adipose tissue, and its level is positively proportionate to the amount of body fat.[19] Like many other hormones, leptin is secreted in a pulsatile manner and shows a significant diurnal variation with higher levels in the evening and early morning hours.[20],[21] Circulating leptin levels reflect primarily the amount of energy stored in the fat, and in addition to that, it controls the acute changes in caloric intake.[20],[21],[22],[23],[24] Its actions are opposed by ghrelin, also known as the hunger hormone. Both the hormones bind with their respective receptors present on the arcuate nucleus of the lateral hypothalamus to maintain energy balance. The principle mechanism in regulating food intake and energy expenditure is mediated through the binding of leptin to the Ob-R leptin receptor. Leptin receptors (Ob-R), a Type I cytokine receptors, are produced from the db gene. Several isoforms of the Ob-R have been isolated through positional cloning of the db gene. Alternative mRNA splicing of this gene encoded in six short (OB-Ra, OB-Rc, OB-Rd, and OB-Rf), long (OB-Rb), and soluble (OB-Re) isoform variants.[25],[26] In obesity, decreased sensitivity of the leptin receptors toward leptin is a major issue which leads to excess leptin production, thereby causing leptin resistance.[20]

Role of leptin in maintaining energy homeostasis

The circulating leptin levels work as a gauge for energy reserves and direct the central nervous system (CNS) to control food intake and energy expenditure accordingly. Leptin puts forth immediate effects by acting on the hypothalamic neurons to regulate appetite. Leptin modulates a complex neural circuit encompassing stimulation of anorexigenic (i.e., appetite-diminishing) and inhibition of orexigenic (i.e., appetite-stimulating) neuropeptides to control food intake through binding with ObRb-receptor in the hypothalamus. Of all the isoforms of the leptin receptor, it is well established that ObRb is the main isoform responsible for the effect of leptin on body weight control. In addition, leptin interacts with the mesolimbic dopamine system, which is concerned in the sensation for the reward of feeding, and the nucleus of the solitary tract of the brainstem contributes to the feelings of satiety.[21]

Neuroendocrine control of leptin

Leptin has been shown to raise the number of synapses on the neurons that secrete the anorexigenic neuropeptide proopiomelanocortin (POMC) and turns down the number of synapses on neurons that secrete the orexigenic neuropeptide NPY (agouti-related peptide [AgRP]/NPY) of the arcuate nucleus of the lateral hypothalamus.[22] In obesity, the hypothalamus fails to identify normal levels of leptin causing more leptin to be released in the bloodstream to make up for it, which leads to leptin resistance.[23]

Generally, leptin binds with LepR to stimulate POMC, which in turn generates α melanocyte-stimulating hormone (α-MSH)[24],[27],[28] that reduces body weight by binding with the melanocortin-3 receptor (MC3R) and MC4R and activating them.[29],[30],[31] Leptin directly depolarizes the POMC neurons and at the same time hyperpolarizes Neuropeptide Y/Gama amino butyric acid (NPY/GABA) neurons, as well as diminishes the release of neuropeptides. The diminished neurotransmitter discharge suppresses its inhibitory effect to the POMC neurons. Both the direct and indirect effects of leptin activate the anorexigenic POMC neurons and amplify the frequency of action potential generation. Moreover, both POMC and NPY neurons express auto-receptors for some of their relevant neuropeptide products (β-endorphin or α-MSH and NPY, respectively) and the activation of these auto-receptors may provide some feedback actions that further modulate the effect of leptin on POMC neurons[32] [Figure 1].{Figure 1}

 Molecular Signaling Pathways Associated with Leptin and Insulin Receptor Signaling



Leptin and insulin receptor (IR) signaling regulate food intake by controlling the expression of orexigenic and anorexigenic neuropeptides in the arcuate nucleus of hypothalamus via their various downstream signaling cascade pathways. The chief signaling pathways employed by leptin to establish energy homeostasis include the Janus kinase (JAK)/signal transducer and activator of transcription 3 (STAT-3)/STAT-5, AMP-activated protein kinase (AMPK), phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR), FoxO1, and Src homology 2 (SH2)-containing protein tyrosine phosphatase 2 (SHP2)/mitogen-activated protein kinase (MAPK) signaling pathway, whereas glucose homeostasis by insulin is mainly regulated through PI3K/Akt/mTOR, FoxO1, AMPK, Ras/MAPK, and suppressor of cytokine signaling (SOCS)-3 signaling pathways.[33] It is clear that leptin and insulin follow some common pathways in the regulation of appetite and energy metabolism. Thus, we proposed that leptin and insulin effect on each other in their downstream signaling cascade pathways.

Janus kinase 2/signal transducer and activator of transcription 3 signaling pathway

The JAK-2/STAT-3 signaling pathway is one of the principle signaling pathways induced by leptin. Leptin on binding to its ObRb receptor activates the JAK-2/STAT-3 pathway. The JAK-2/STAT-3 signaling pathway comprises a family of nonreceptor tyrosine kinases (JAKs) and transcription factors (STATs) that are regulated by the phosphorylation on specific serine and tyrosine residues present in the cytoplasmic region of the ObRb receptor.[34] The JAK family consists of four members: JAK-1, JAK-2, JAK-3, and Tyk2[35] and the STAT transcription factor family consists of seven members: STAT-1, STAT-2, STAT-3, STAT-4, STAT-5A, STAT-5B, and STAT-6.[36] The ObRb receptor consists of various tyrosine residues that provide a docking site for the downstream signaling of the STAT proteins. When leptin binds to the ObRb receptor, auto-phosphorylation of Tyr1077 and Tyr1138 residues recruit STAT-3 and STAT-5b, respectively. The STAT-3 proteins are then phosphorylated by JAK-2 to form dimers that translocate to the nucleus to act as the transcription factors for the expression of the POMC gene. JAK-2 activation by leptin occurs through a proline-rich “box 1” motif on the ObRb receptor. JAK-2 activation further recruits insulin receptor substrate-1 and -2 (IRS-1 and IRS-2) which are activated through phosphorylation.[37] Phosphorylated IRS then initiates PI3K and its downstream signaling molecules. An experiment conducted on rat liver also indicated a direct and positive crosstalk between insulin and leptin at the level of JAK-2 and STAT-5b tyrosine phosphorylation.[38]

Phosphatidyl inositol 3-kinase/Akt/mammalian target of rapamycin signaling pathway

The PI3K/AKT/mTOR pathway is an important intracellular signaling pathway for the cell cycle regulation mechanism. Both leptin and insulin play a crucial role in the activation of this cascade pathway, thus making it a relevant point of crosstalk between the leptin and insulin signaling pathways. Although leptin can independently activate the PI3K/Akt/mTOR pathway by phosphorylating the IRS-1 and IRS-2, it mainly acts through some of the components of the insulin signaling cascade. Circulating insulin molecules bind to the transmembrane IR and recruits different IRSs that are tyrosine phosphorylated by the receptor's intrinsic kinase activity. This was verified in an experiment on C2C12 myotubes where leptin and insulin both stimulated the activation of PI3K downstream signaling pathway and was further followed by the recruitment of GLUT4 and activation of glucose transport and glycogen synthesis.[39] IRSs exert PI3K signaling pathway activation via its association with the regulatory subunit, p85, thus stabilizing the p110 subunit of the catalytic domain of PI3K.[40] The stimulation of PI3K further leads to the activation of serine/threonine kinases such as phosphoinositide-dependent kinase 1, which in turn activates Akt triggering the downstream signaling. Leptin has also been seen to stimulate the PI3K activity of the hypothalamic IRS-2.[34] However, administration of the pharmacological inhibitors of PI3K leads to the obstruction of leptin-induced hyperpolarization of NPY/AgRP neurons and hence block the anorectic effect of leptin.[41] Leptin activates ribosomal S6 kinase which is an important physiological substrate of mTOR kinase in the hypothalamus.[42] The insulin-PI3K pathway also hyperpolarizes POMC neurons, making them less sensitive to leptin.[43] Further, chronic activation of the PI3K pathway in POMC neurons causes leptin resistance and hyperphagia in mice with POMC neuron-specific deletion of PTEN.[44] This suggests a strong inter-relationship in the signaling pathways involving both leptin and insulin and thus provides relevance for the crosstalk between them [Figure 2] and [Figure 3].{Figure 2}{Figure 3}

FoxO1 signaling pathway

Insulin regulates the action of the forkhead transcription factor (FOXO) by Akt-mediated phosphorylation.[45] FOXO is a downstream target of insulin signaling. It regulates metabolism in various organs such as the liver, pancreas, muscle, adipose tissue, and hypothalamus.[33] FoxO1 binds to AgRP and NPY and inhibits the expression of POMC neurons in the hypothalamus.[46] In liver, FoxO1 regulates glucose homeostasis in the pancreatic β-cells and surrounding tissues. Phosphorylation by AKT activates FoxO1 which sequentially causes hepatic insulin resistance and loss of pancreatic β-cells via increased apoptosis.[47] FoxO6, another FOXO protein, acts as nuclear transcription factors to inhibit insulin or insulin-like growth factor 1 and regulates gluconeogenesis via phosphoenol pyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase)[48] [Figure 3].

AMP-activated protein kinase signaling pathway

AMP-activated protein kinase (AMPK) acts in response to hormonal and nutrient signals of the hypothalamus and regulates food consumption.[49] AMPK controls energy expenditure by varying NAD + metabolism and sirtuin-1 (Sirt-1) activity[50] and further modulates the energy level by interfering with glucose uptake and FA oxidation.[51] Leptin inhibits arcuate and paraventricular hypothalamic AMPK activity, and its inhibition is essential to restrict food intake.[52] There are several mechanisms for the inhibitory actions of leptin. To begin with ghrelin, it stimulates AMPK in NPY/AgRP of the arcuate nucleus and in the ventromedial hypothalamic nucleus, thereby stimulating the AMPK-dependent presynaptic pathway. Second, adiponectin also stimulates hypothalamic AMPK. Third, AMPK regulates energy consumption via thyroid hormone or leptin.[53] Sirt-1 improves insulin sensitivity. In an in vivo study of diet-induced obese mice and db/db mice, Sirt-1 protein in the hypothalamus increases food intake. In a model of central insulin resistance, artificial expression of wild-type Sirt-1 by adenovirus micro-injection in the mediobasal hypothalamus represses FoxO1-induced hyperphagia and thereby modulates liver metabolism and pancreatic β-cell function.[54]

Ras/extracellular signal-regulated kinase/Src homology 2-containing protein tyrosine phosphatase 2/mitogen-activated protein kinase signaling pathway

Both leptin and insulin play a pivotal role in the stimulation of the MAPK signaling pathway. MAPKs are a highly conserved family of serine/threonine protein kinases that are involved in a variety of cellular metabolic processes, such as proliferation, differentiation, apoptosis, and survival.[55] Leptin stimulates extracellular signal-regulated kinase (ERK)/MAPK signaling pathway via SHP2. Leptin binding to ObRb induces JAK-2 activation followed by phosphorylation of the Tyr985 amino acid residue. This creates a binding site for the carboxyl-terminal SH2 domain of SHP2.[56] Leptin also activates the MAPK pathway independently of SHP2. This is mediated via binding of growth factor receptor-bound protein-2 (Grb-2) to JAK-2.[57] Insulin plays an equally important role in the activation of the MAPK signaling cascade. The interaction of insulin to its transmembrane receptor triggers mitogenic cellular responses. This was evident from a study where insulin stimulated the MAPK pathway in 3T3-L1 fibroblasts and 3T3-L1 adipocytes.[58] The ERK/MAP kinase signaling pathway also controls insulin-like receptor (inr) gene expression and regulates glucose metabolism as seen in Drosophila strains.[59]

 Leptin Resistance



The reduced effectiveness of leptin in homeostasis to prevent food consumption has been designated as leptin resistance. Obesity and increased adiposity are generally allied with elevated leptin levels.[60] Defects of transport of leptin through the blood–brain barrier,[61] malfunctions in the LRb signaling pathway,[62],[63],[64] defective neuronal signaling, and malfunctions in the hypothalamus of eating circuits[65],[66] all may contribute in leptin resistance. In addition, it was suggested that obesity causes a decrease in leptin efficiency. Leptin resistance has been depicted in various experimental models of aged individuals,[67] seasonal obese rodents,[68] and diet-induced obesity-prone rodents. Any lesion in the arcuate nucleus may hamper leptin signaling. A higher concentration of free leptin increases the production of more SOCS protein which may, in turn, lead to insulin resistance.[69] Leptin transport across the blood–brain barrier is mediated via LepRa and LepRe.[70] Therefore, improper binding of leptin to its receptors (LepR) leads to the presence of excess leptin in the bloodstream, which may also cause leptin resistance.[71]

Leptin resistance due to defective leptin transport across the blood–brain barrier

Leptin is internalized across the blood–brain barrier upon binding to the receptor by clathrin-coated vesicles which are known to exist in tanycytes. Tanycytes are specialized hypothalamic glia-like cells that stretch through the ependymal surface of the third ventricle, lining circumventricular organ, to the floor of the fourth ventricle of the brain. They project through the hypothalamic arcuate nucleus and the median eminence forming a barrier between the blood and cerebrospinal fluid (CSF) and are capable of transporting macromolecules via transcytosis.[72],[73] However, it has been seen that LepR activation plays a crucial role in the uptake of leptin across the hypothalamus. This explains the involvement of defective LepR signaling in leptin resistance in both hypothalamic tanycytes and neurons.[74] According to an experiment, it was evident that the amount of leptin in CSF was less as compared to that of the serum in diet-induced experimental obese rats.[75]

Leptin-induced leptin resistance

Leptin resistance is commonly associated with hyperleptinemia, and leptin can induce SOCS-3 as well as Protein tyrosine phosphatase 1B (PTP1B), which implies its own resistance as a feedback action. Leptin resistance is commonly associated with hyperleptinemia. High leptin levels in the blood can induce overexpression of SOCS-3 as well as PTB1B, which imply its own resistance via a feedback mechanism. Endogenous SOCS-3 expression participates in leptin resistance by inhibiting tyrosine phosphorylation of the long isoform of receptor, OBRb, at Tyr985 and Tyr1138 by competing with SHP2 and STAT-3, respectively, which has a high-affinity binding site for SOCS-3 during IL-6 receptor signaling.[76],[77] On the contrary, PTP1B negatively regulates leptin signaling through dephosphorylation of JAK-2.[78] This concept was further supported in a rodent (experimental model), where rats were given chronic leptin administration in the CSF. Despite the fact that these rodents initially lost weight, their body weights normalized over time regardless of ongoing leptin administration. Additional acute leptin administration became futile to induce any anorexigenic effect, leading to leptin resistance[79] [Figure 1] and [Figure 3].

Stress and Leptin Resistance

Excess feeding leads to deposition of adipocytes which trigger surplus leptin production and improper protein folding in the endoplasmic reticulum, resulting in cellular stress. Cortisol, the “stress hormone,” binds with glucocorticoid receptors after removing the bound HSP90 from it and the cortisol bound receptor complex forms a dimer which acts upon the ob gene in the fat cells to produce more leptin. Hence, excess leptin in the blood is also a result of stress and leads to leptin resistance[80] [Figure 3].

Janus-activating kinase-signal transducer and activator of transcription-suppressor of cytokine signaling-3 and leptin resistance

Effect of SOCS-3, also referred to as the JAK-binding protein, attenuates receptor signaling by multiple mechanisms. Acting on leptin receptors, it disarrays the signal transduction via JAK-2-STAT-3 pathways. Signal transduction system of diverse cytokines such as leptin induces SOCS-3 expression, and in turn, leptin is also inhibited by SOCS-3 protein, which is a leptin-inducible inhibitor. Leptin-induced SOCS-3 expression and its activation inhibit JAK-2 and STAT-3 phosphorylation at the downstream cascade of leptin receptor signaling. Such inhibition of JAK-2-STAT-3 phosphorylation by SOCS-3 protein is the cause of leptin resistance and consequent leptin function.[81] SOCS-3 acts as a negative feedback inhibitor of leptin signaling, thus SOCS-3 over-expression in leptin-responsive cells is a potential cause for leptin resistance as observed in obese individuals. Obesity generates more circulating leptin which increases SOCS-3 protein level in the hypothalamic leptin-responsive neurons and blunts leptin action.[82] Leptin binds with the extracellular domain of the long form of leptin receptor (LRb) and activates JAK-2 tyrosine kinase.[81] After autophophorylation JAK-2 tyrosine kinase produce the active forms of Tyr 985 and Tyr1138 at the intracellular domain of LRb -2. STAT-3 binds with activated Tyr 1138 and gets stimulated.[82] Activated STAT-3 controls SOCS-3 and POMC transcription and hinders AgRP transcription. Activated Tyr 985 binds SHP2 (also known as PTPN11) and phosphorylates growth factor receptor binding 2 which in turn triggers ERK. In addition, activated Tyr 985 may even bind SOCS-3 upon its extended stimulation.[83] STAT-3, instigated by leptin, activates the negative feedback regulator SOCS-3, which impedes leptin-triggered signal transduction. In obesity, elevated leptin might boom the activity of LRb/STAT-3 signaling in POMC neurons of the CNS which in turn will increase the silent SOCS-3 expression, thereby damaging LRb sensitivity and developing leptin resistance[63] [Figure 1] and [Figure 3].

Activation of matrix metalloproteinases and leptin resistance

Matrix metalloproteinases (MMPs) such as MMP-2, MMP-8, and MMP-9 are a group of proteolytic enzymes that are activated upon activation of inflammatory responses induced by obesity, in tumor growth and metastasis. MMPs' physiological functions include degradation of extracellular matrix proteins during organogenesis, cellular migration, remodeling of the vasculature, and tissue repair.[84],[85] MMP-2 acts as a key regulatory factor in initiating a primary innate immune response. It induces mitochondrial nuclear stress signaling by activating the nuclear factor (NF)-κB, Nuclear factor of activated T cells (NFAT), and Interferon regulatory factor (IRF) transcriptional pathways. However, recent reports have suggested that obesity induced by high-fat diet (HFD) leads to the activation of MMP-2 in the hypothalamus, which further impairs leptin signaling by cleaving the extracellular domain of the leptin receptor and promoting leptin resistance. Knockout of this MMP-2 restored the expression of the leptin receptor and alleviated leptin and insulin resistance.[86]

 Insulin Resistance



IRs and insulin signaling molecules are widely distributed throughout the CNS. IR-mediated signaling plays a vital role in the regulation of cellular energy expenditure and fuel metabolism. The reason behind insulin resistance can be attributed differently in lean and obese subjects. In case of lean subjects suffering from lipodystrophy syndrome, insulin resistance occurs due to leptin deficiency.[87] A decrease in insulin-stimulated GLUT-4 activity reduces glycogen synthesis in insulin-stimulated skeletal muscles, thereby causing insulin resistance.[88] Protein tyrosine phosphatase 1B is a negative modulator of insulin receptor; it dephosphorylates and inactivates the IR, thereby dampens the insulin signaling cascade.[87],[88]

Excess intracellular lipid and insulin resistance

Due to the presence of excess intracellular lipid in obesity, an inhibition of insulin-stimulated IRS-1 tyrosine phosphorylation occurs which reduces the association of IRS-1 with PI3K. In a research, observation in patients and mouse models of lipody strophy determined that buildup of intracellular metabolites such as fatty acyl CoA and diacylglycerol (DAG) in the hepatic cells and skeletal muscles leads to insulin resistance, which supports the fact that increased insulin sensitivity in the hepatocytes is due to reduction in weight in type-2 diabetic patients, without any change in circulating cytokines in the adipocytes such as IL-6, leptin, and resistin.[89] Several in vitro studies have shown that if pancreatic islets were incubated with leptin, insulin secretion decreased from the β-cells.[90],[91],[92] The relationship between FA and glucose metabolism could be clarified by Randle cycle (glucose-FA cycle). This cycle shows that excess fat metabolism hinders the oxidation of glucose and diminishes glucose utilization. Free fatty acids (FFAs) may also downregulate GLUT4 gene expression and PI3K activity associated with the insulin signaling pathway. FFAs hamper glucose transport due to the accumulation of DAG and fatty acyl CoA that ultimately repress insulin signaling.[93] Obesity-associated hepatic insulin resistance is the consequence of such elevated plasma FFA levels.[94] Further, intra-myocellular lipid content increases due to decreased mitochondrial function, which in turn leads to insulin resistance. Defects in the pancreatic β-cells can also result in impaired insulin action.[95] Diabetic patients have decreased insulin-stimulated muscle glycogen synthesis. This may be due to impaired insulin-stimulated glucose transport and phosphorylation in those obese diabetic patients.[96] In general, insulin binding with its receptor activates it which engenders a signaling pathway to phosphorylate IRS-1; however, when plasma FA levels are high, it blocks the activation of IRS-1 to associate with PI3K[97] as the lipid metabolites activate protein kinase C (PKC)-θ via serine-threonine kinase pathway blocking the tyrosine phosphorylation of IRS-1 by activated insulin receptor, which in turn decreases the PI3K activity.[98] These lipids also drop off phosphorylation of IRS-2 via serine kinase pathway activating PKC-ε, which plays a pivotal role in regulating insulin action in hepatocytes.[99],[100] Hence, increased level of fatty acyl-CoA in the muscle and liver impairs activation of IRS-1 and IRS-2 with PI3K activity[101],[102] [Figure 3].

Impaired mitochondrial activity-induced insulin resistance

Loss of mitochondrial activity due to old age leads to insulin resistance. This impaired function of mitochondria is due to an increase in the intra-myocellular fat content, leading to decreased mitochondrial ATP synthesis.[103] SHP2-SH2 associates with phosphorylated IRS -1 to promote its dephosphorylation during insulin stimulation to reduce insulin signaling. Insulin action is inversely controlled by protein-tyrosine phosphatase 1B through the dephosphorylation of the IR. Further, a reduction in IR number and not affinity to receptor reduces insulin binding to monocytes and adipocytes in type-2 diabetic patients.[104] A defect in IRS-1 and IRS-2 function found in type-2 diabetic patients and nondiabetic obese patients is due to the failure of insulin to increase the binding of the p85 subunit of PI3K with IRS-1. This may be due to the impaired regulation of PI3K gene by insulin which leads to muscle insulin resistance in vivo[104] [Figure 3].

Role of tumor necrosis factor in insulin resistance

Adipocytes are a major source of TNF-α production, which is overexpressed in the muscle and adipocytes in obese people, leading to serine phosphorylation of IRS-1, while reducing the tyrosine kinase activity of the IR,[105] which then leads to impaired insulin signaling. In obesity, excess TNF-α limits the augmentation of adipocytes via changes in lipoprotein lipase but in turn causes insulin resistance.[106] Further, a polymorphism in TNF-α promoter at 308 position, replacing guanine by adenine, was observed, which was named as TNF-2 as it opposed TNF-1 and its expression increases the activity or production of TNF-α protein or mRNA which ultimately leads to insulin resistance.[107]

Role of insulin receptor substrate-phosphatidyl inositol 3-kinase in insulin resistance

PI3K mediates its metabolic effects after being activated by insulin, and its p85 subunit is the main response pathway. The insulin by modulating PKB/Akt pathway regulates the transport of glucose and synthesis of glycogen, protein, and lipid and inhibits hepatic neoglucogenesis. Obese patients suffering from insulin resistance shows decreased expression of both PI3K and PKB in the skeletal muscle[108],[109] [Figure 2].

 Connection between Leptin Resistance and Insulin Resistance



Although leptin and insulin signal cascade follow different transduction pathways, they both act on the same hypothalamic area to control eating behavior.[110] It was found that the co-infusion of leptin and insulin enhances leptin-induced JAK-2-STAT-3 signal transduction.[38] A number of studies have demonstrated that there must be connections between the mechanism of leptin and hepatic glycogen metabolism. Leptin works directly on the liver which is the main site of carbohydrate metabolism. Literature has indicated that leptin reproduces the anabolic effects of insulin in the liver. A study carried out by Morton et al. on perfused mouse liver has revealed that leptin boosts the inhibitory actions of insulin on gluconeogenesis and glycogenolysis in liver and results in the modulation of some of the initial molecules of IRS pathway.[108] Chronic intake of leptin improves glucose tolerance via lessening the calorie intake and body fat.[111],[112],[113] Some studies revealed that leptin plays a major role in the choice of food and energy homeostasis under various nutritional statuses.[114],[115],[116] In hyperphagia, the action of leptin on gluconeogenesis in the liver was blocked, which led to insulin resistance. In leptin-resistant obese individuals, the permeability of leptin through the blood–brain barrier is decreased in HFD-induced obesity even though high plasma leptin level was present. This impaired transport of leptin across the blood–brain barrier is one of the causes of leptin resistance.[117] Insufficiency of leptin signaling in the hypothalamus (provoked by hyperleptinemia in obese persons) causes disturbing appetite and leads to hyperglycemia and hyperinsulinemia.[118],[119],[120],[121] Obesity in a combination with HFD is also associated with the presence of C-reactive protein (CRP) which is a marker of chronic inflammation. Remarkably, leptin itself brings on hepatic CRP production, which binds to leptin and inhibits its interaction with LEPR, thus leading to leptin resistance.[122],[123] In Fao cells, it has been seen that leptin pretreatment intensified the IR tyrosine phosphorylation and IRS-1 but inhibited IRS-2. In HepG2 human hepatoma cells, leptin has been shown to antagonize insulin-induced downregulation of PEPCK expression, decrease insulin-stimulated tyrosine phosphorylation of IRS-1, and enhance IRS-1-associated PI3K playing a key role in insulin resistance.[124] In polycystic ovarian syndrome (PCOS) activity,[125] SOCS-3 which acts as a feedback inhibitor to ObRb signaling, mediating leptin resistance, was also capable of attenuating insulin signaling, thereby inducing severe metabolic and endocrinal disorder; 50%–75% of the patients showed severe insulin resistance and prevalent obesity ranging between 6% and 100% among different populations.[126],[127] The leptin levels in the serum of patients with severe conditions of PCOS were also seen to be relatively high as compared to healthy individuals[128] which indicated leptin resistance in such patients and was found to be quiet relevant with a case of prevalent obesity seen in them. Further, the drug metformin or glucophage which is prescribed for the treatment of type-2 diabetes was also found to be effective in treating PCOS, maintaining energy metabolism,[129] and reducing weight.[130] This assured definite crosstalk lying between the insulin and leptin signaling pathways.

Role of the Janus-activating kinase-signal transducer and activator of transcription pathway

The tyrosine phosphorylation of IR instigated by insulin phosphorylates IRS-1 and IRS-2 which in turn bind to a p85α regulatory subunit of PI3K and gets associated with p110 catalytic subunit. This leads to activate downstream targets via PKB.[131] Leptin binding to its hypothalamic receptors causes tyrosine-phosphorylation of JAK-2 and STAT-3. Leptin is less effective in activating IRS and thereby PI3K than that of insulin. It was found that tyrosine phosphorylation at JAK-2 or STAT5b was much higher when leptin and insulin co-stimulated rat liver cells than that of their effects alone, but no change in the maximal phosphorylation of STAT-3, IRS-1, IRS-2, and AKT was observed in either treatment.[41],[132] Thus, it can be stated that JAK-2 renders the merging points between the crosstalk of these two hormones signaling. In a normal homeostatic condition, leptin enhances insulin signaling by the activation of IRS2 via phosphorylated JAK-2 at leptin receptor,[133] which activates PI3K in muscle via IRS-2 and SH2B1.[41],[134] Also that, PI3K and IRS-2 have a role in the anorexic response to leptin in the hypothalamus.[41],[131] According to speculation, it may show the decreased ability of PI3K to respond to leptin via IRS-1 or IRS-2 which points to improper leptin function, loss of leptin regulation, and excess fat build-up. The PI3KR1 gene generates PI3K regulatory subunit isoforms p85α, p55α, and p50α by alternative splicing which negatively regulates catalytic activity to various levels,[135] and p85α displays the most powerful effect[136],[137],[138] [Figure 3].

Role of cytokines-Janus-activating kinase-signal transducer and activator of transcription-suppressor of cytokine signaling

TNFα and IL-6 are the most distinguished cytokines which are over-expressed within the bloodstream of obese people; however, IL-6-induced signaling is only mediated via JAK and STAT-3.[139] IL-6 binds to its receptors: IL-6Rα chain (for specificity) and GP130 signaling chain (common receptor for IL-6 type cytokines),[138] and the receptor complex activates intracellular JAK-2 and STAT-3, thereby modulating gene expression of increased SOCS-3. Although IL-6Rα chain is expressed mainly by hepatocytes and immune cells, other cells counter to IL-6 by IL-6 trans-signaling, where the α-chain (cleaved from the cell surface) forms a complex with the IL-6 to bind with predominantly expressed GP130 to instigate JAK-STAT-3-mediated downstream signaling,[139],[140] which brings us to the fact that the signaling of leptin and insulin is disrupted by means of impaired JAK-STAT-3 pathway due to the regulation of SOCS.[141] SOCS proteins also have a role in the attenuation of the IR. Expression of SOCS-3 signaling molecules has been reported to be elevated in the white adipose tissue of mice made obese by a HFD in rodent models of obesity and diabetes.[81],[113] Some key metabolic hormones have been shown to provoke insulin resistance in adipocytes.[140],[142],[143] Since the expression of SOCS-3 in the adipocytes was found to be increased by growth hormone, angiotensin II and resistin, therefore, SOCS-3 has been proposed as a potential mediator of insulin resistance.[144],[145],[146] SOCS proteins interrupt insulin signaling via binding to the insulin receptor and/or by targeting IRS-1 and IRS-2 for their proteasomal degradation. SOCS-3 binds to phosphorylated tyrosine 960 of the insulin receptor subunit (IRS) and prevents activation of STAT-5b.[147] In Cos-7 cells, SOCS-3 reduces phosphorylation of IRS-1 and its subsequent coalition with p85, the modulatory subunit of PI3K.[148] A recent report revealed the supporting role for endogenous SOCS-3 in the development of insulin resistance coupled with infection with a hepatitis C virus (HCV). In human hepatoma cell lines, HCV improves SOCS-3 expression which leads to ubiquitination and degradation of IRS-1 and IRS-2.[149] In obesity, infection, injury, and aging, pro-inflammatory cytokines such as IL-6[150] and the TNFα[105] possess a pivotal role in insulin resistance. TNFα modulates gene expression in adipocytes and thereby regulates insulin resistance and obesity. TNF-α is produced endogenously in adipocytes, and in the case of obesity, its expression is increased which leads to hyperinsulinemia. These cytokines increase the expression of SOCS-3 by activating the pathways mediated by STAT and NF-κB. SOCS-1 and SOCS-3 regulate cytokine signaling and insulin regulation. According to Steppan et al., SOCS-3 binds with an IR which prevents phosphorylation of IRS-2 and elevated levels of SOCS-3 decreases IRS-1 and IRS-2 levels by their ubiquitination[146],[150],[151] [Figure 3].

Role of phosphodiesterase-3B-cAMP pathway

The phosphodiesterase-3B (PDE3B)-cAMP pathway is crucial in leptin signaling in the peripheral tissues of hypothalamus.[152] Normal leptin signaling involves PI3K-dependent activation of PDE3B and decreased cAMP levels in the ARC.[132] The PDE3B-cAMP pathway interacts through the JAK-2/STAT-3 signaling cascade to establish energy homeostasis.[152] A study on male FVB/N mice fed with HFD showed increased obesity along with hyperleptinemia and hyperinsulinemia. Further, the anorectic effect of leptin in HFD-induced obese mouse was reduced as exogenous leptin failed to show any hypothalamic PDE3B activity and p-Akt expression, whereas the expressions were normal in low-fat-diet mice.[153] This indicates that impaired PDE3B-cAMP signaling pathway leads to both insulin and leptin resistance in association with obesity.

Impaired VMH amylin signaling

Amylin is a 37 amino acid residue peptide hormone, co-secreted with insulin from the pancreatic β-cells.[154] Amylin is reported to regulate body glycemic concentrations similar to that of insulin.[155] Impaired VMH amylin signaling thus reduces the amylin concentrations which further effect insulin signaling and lead to insulin resistance. Again, amylin also stimulates the ARC and ventromedial leptin signaling in the hypothalamus and thus maintains the food–energy balance.[156] A report suggested that impairing VMH calcitonin receptor-mediated signaling in HFD obese mouse reduced leptin binding and hence conferred leptin resistance, while it also consecutively led to increased obesity and insulin resistance.[157] Thus, low amylin concentrations or impaired VMH amylin signaling can both result in leptin and insulin resistance.

Increased expression of IKK epsilon, endospanin 1, and cannabinoid receptor 1

IKK epsilon (IKKε) is a serine/threonine kinase enzyme that regulates inflammatory response induced by the activation of NF-κB.[158] Experiments conducted on whole-body IKKε knockout mice that were fed on HFD showed sensitivity to leptin and enhanced energy homeostasis. On the contrary, IKKε upregulation led to both insulin and leptin resistance.[159] Another integral membrane protein, endospanin 1 acts as a negative regulator to the receptor.[160] Overexpression of endospanin-1 leads to a decrease in the ObRb cell surface expression as it retains the receptor within the cell membrane.[161] Unavailability of the leptin receptor to leptin molecule further complements leptin resistance.[162] Cannabinoid receptors are another group of G-protein-coupled receptors that are involved in various physiological functions, including feeding, glucose homeostasis, and lipid metabolism.[163] The cannabinoid receptors exist in two isoforms, CB1 and CB2, of which the CB1 is associated with leptin and insulin resistance.[164],[165] The CB1 receptor overexpression hindered leptin and insulin signaling, whereas blockage of the receptor sensitized the resistance.[166]

 Obesity and Leptin Resistance Foster Insulin Resistance



Obesity is a physiological condition associated with elevated plasma FFA levels. Adipose tissue is not only a storage site for excessive calories in the form of fat but also secretes a large number of biologically active adipokines, inflammatory cytokines, etc., Nevertheless, leptin is being considered a physiological link between obesity and insulin resistance. Obesity or increased adiposity is generally allied with elevated leptin levels. It blunts leptin efficiency leading to hyperleptinemia and leptin resistance.[19] Excess cellular FFA due to lipid overload increases intracellular long-chain fatty acyl CoA which in turn activates DAG and PKCs, which block insulin receptor signaling. These increased FFAs suppress the expression of GLUT-4, the glucose transporter, which promotes insulin resistance.[88] Deposition of excess lipid leads to excess production of leptin and improper folding of signaling proteins and activate the unfolded protein response pathways, resulting in cellular stress and enhancement of stress response. It causes dimerization of cortisol bound receptor complex, after the removal of HSP90 bound to it, which acts upon the ob gene in the fat cells and induces the production of more leptin.[167] Leptin-induced SOCS-3 expression and its activation inhibit JAK-2 and STAT-3 phosphorylation at the intracellular domain of leptin receptor which in turn blunts the sensitivity of leptin causing its own resistance.[81] Insulin-stimulated PI3K activity depends on the activation of both IRS-1 and IRS-2, whereas JAK-2 of leptin receptor-mediated PI3K activity depends on the activation of IRS-2 of IR complex.[39] In leptin-resistant condition, excess SOCS-3–mediated dephosphorylation of JAK2 in LEPR fails to activate IRS2 at IR resulting in insulin resistance.[150] In addition, SOCS-3 also directly inhibit tyrosine 960 phosphorylation of IR. On the other hand, insulin regulates the action of the forkhead transcription factor by Akt-mediated inhibition of FOXO phosphorylation.[45] The AKT-mediated nuclear translocation of dephosphorylated FOXO induces further FOXO expression along with transcription of its target genes PEPCK and G6Pase, resulting in increased hepatic gluconeogenesis and hyperglycemia. FOXO inhibits anorexigenic POMC neuron and stimulates orexigenic AgRP/NPY neuron, which results in increased additional food intake that stimulates further leptin resistance. Again, insulin-stimulated AKT2 expression stimulates GSK3 activity which not only diminishes the activity of glycogen synthase but also blocks the Tyr phosphorylation of IRS-1. The crosstalk between leptin and IR signaling molecules, leptin, FFA, SOCS-3, JAK-2, PKC, FOXO, and other different signaling molecules ultimately potentiates further leptin resistance and subsequent insulin resistance [Figure 3].

 Conclusion



In this review, we tried to put an overview of the current concepts of insulin and leptin. They target the intracellular mechanisms activated or suppressed and the crosstalk between them which creates resistance against these two hormones [Figure 4]. It is clear from the existing data that hypothalamic circuits are necessary to control energy homeostasis and body weight regulation. Excess dependencies on machines and technology, improper timing of food intake, sedentary lifestyle,[1] and consumption of high-calorie diet result in lipid accumulation in the liver and skeletal muscles at a larger content.[2] Prevalence and complications allied with obesity impose a major impact on the physiological system, specifically appetite regulation and energy metabolism.[168] The pancreatic hormone insulin and adipose tissue-derived cytokine leptin are chief modulators of the energy balance maintenance system. Obesity disrupts this energy homeostasis and engenders leptin and insulin resistance. It has already established that lesion in the arcuate nucleus of hypothalamus could change body weight and food intake capacity. Hyperleptinemia allied with obesity and HFD induces more SOCS-3 expression, which further blocks leptin signaling at the level of leptin receptor[81] and insulin signaling pathway via promoting ubiquitin-mediated degradation of IRS. On the other hand, SOCS-3 withdrawal strongly prevents diet-induced obesity.[168] From the above critical discussion, it can be said that obesity increases serum leptin level followed by reduced leptin sensitivity and leptin resistance which increases the production of SOCS-3. This increased level of SOCS-3 leads to insulin resistance in the skeletal muscle and liver. This review provides an insight into the reason why there is a metabolic risk among people with a higher degree of adiposity, leptin resistance, and increased probability of incidence of insulin resistance.{Figure 4}

Acknowledgment

We thank the West Bengal State University, Kolkata, India, and the University of Gour Banga, Malda, India, for their support. Authors are also thankful to SERB (Department of Science and Technology, Government of India) for funding (Ref. No. SR/FT/LS - 132/2010) to Dr. Biplab Giri.

Financial support and sponsorship

SERB (Department of Science and Technology, Government of India) funding (Ref. No. SR/FT/ LS-132/2010).

Conflicts of interest

There are no conflicts of interest.

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