The liver is an essential metabolic organ, and its metabolic activity is tightly controlled by insulin and other metabolic hormones. Glucose is metabolized into pyruvate through glycolysis in the cytoplasm, and pyruvate is completely oxidized to generate ATP through the TCA cycle and oxidative phosphorylation in the mitochondria. In the fed state, glycolytic products are used to synthesize fatty acids through de novo lipogenesis. Long-chain fatty acids are incorporated into triacylglycerol, phospholipids, and cholesterol esters in hepatocytes, and these complex lipids are stored in lipid droplets and membrane structures, or secreted into the circulation as VLDL particles. In the fasted state, the liver secretes glucose through both breakdown of glycogen (glycogenolysis) and de novo glucose synthesis (gluconeogenesis). During pronged fasting, hepatic gluconeogenesis is the primary source of endogenous glucose production. Fasting also promotes lipolysis in adipose tissue to release nonesterified fatty acids which are converted into ketone bodies in the liver though mitochondrial β oxidation and ketogenesis. Ketone bodies provide a metabolic fuel for extrahepatic tissues. Liver metabolic processes are tightly regulated by neuronal and hormonal systems. The sympathetic system stimulates, whereas the parasympathetic system suppresses, hepatic gluconeogenesis. Insulin stimulates glycolysis and lipogenesis, but suppresses gluconeogenesis; glucagon counteracts insulin action. Numerous transcription factors and coactivators, including CREB, FOXO1, ChREBP, SREBP, PGC-1α, and CRTC2, control the expression of the enzymes which catalyze the rate-limiting steps of liver metabolic processes, thus controlling liver energy metabolism. Aberrant energy metabolism in the liver promotes insulin resistance, diabetes, and nonalcoholic fatty liver diseases (NAFLD).

Inflammation associates with peripheral insulin resistance, which dysregulates nutrient homeostasis and leads to diabetes. Inflammation induces the expression of SOCS proteins. We show that SOCS1 or SOCS3 targeted IRS1 and IRS2, two critical signaling molecules for insulin action, for ubiquitin-mediated degradation. SOCS1 or SOCS3 bound both recombinant and endogenous IRS1 and IRS2 and promoted their ubiquitination and subsequent degradation in multiple cell types. Mutations in the conserved SOCS box of SOCS1 abrogated its interaction with the elongin BC ubiquitin-ligase complex without affecting its binding to IRS1 or IRS2. The SOCS1 mutants also failed to promote the ubiquitination and degradation of either IRS1 or IRS2. Adenoviralmediated expression of SOCS1 in mouse liver dramatically reduced hepatic IRS1 and IRS2 protein levels and caused glucose intolerance; by contrast, expression of the SOCS1 mutants had no effect. Thus, SOCS-mediated degradation of IRS proteins, presumably via the elongin BC ubiquitin-ligase, might be a general mechanism of inflammation-induced insulin resistance, providing a target for therapy.Insulin and insulin-like growth factors exert many biological effects through receptor-mediated tyrosine phosphorylation of insulin receptor substrates (IRS 1 proteins), including IRS1, IRS2, IRS3, and IRS4 (1, 2). IRS proteins coordinate multiple signals through the PI 3-kinase 3 Pkb/Akt and the Grb2/Sos 3 Ras cascades (1, 2). In mice, IRS1 mediates the effects of insulin and IGF1 on somatic cell growth, whereas IRS2 is essential for nutrient homeostasis (3, 4). Mice lacking IRS1 or IRS2 display peripheral insulin resistance, which is a major determinant of type 2 diabetes (5-10). However, IRS1Ϫ/Ϫ mice never develop diabetes because of life-long compensatory hyperinsulinemia, whereas disruption of IRS2 causes severe glucose intolerance and diabetes (4). Dysregulation of IRS2 is especially problematic, because it regulates transcription factors in ␤-cells that are essential for glucose sensing and insulin secretion (1, 11). IRS proteins also integrate heterologous signals that negatively regulate the insulin-signaling cascade. Proinflammatory cytokines or insulin activate the c-Jun Nterminal kinase (JNK), which promotes serine phosphorylation of IRS1 and IRS2 that inhibits coupling to the activated insulin receptor (12). In addition, IRS proteins are decreased in people and rodents with diabetes (13-16). Our recent studies reveal that IRS proteins are ubiquitinated and subsequently degraded by the 26 S proteasome during insulin stimulation or during cellular stress, but the mechanisms that recruit ubiquitinligases to the IRS proteins are unknown (17,18).Insulin resistance is a common consequence of physiological stress, owing at least in part to the production of proinflammatory cytokines during infection or injury, pregnancy, growth and aging, or chronic obesity (19 -22). Many proinflammatory cytokines up-regulate suppressors of cytokine signaling (SOCS) proteins, including eight isoforms that c...

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The brain controls energy homeostasis and body weight by integrating various metabolic signals. Leptin, an adipose-derived hormone, conveys critical information about peripheral energy storage and availability to the brain. Leptin decreases body weight by both suppressing appetite and promoting energy expenditure. Leptin directly targets hypothalamic neurons, including AgRP and POMC neurons. These leptin-responsive neurons widely connect to other neurons in the brain, forming a sophisticated neurocircuitry that controls energy intake and expenditure. The anorexigenic actions of leptin are mediated by LEPRb, the long form of the leptin receptor, in the hypothalamus. LEPRb activates both JAK2-dependent and -independent pathways, including the STAT3, PI 3-kinase, MAPK, AMPK, and mTOR pathways. These pathways act coordinately to form a network that fully mediates leptin response. LEPRb signaling is regulated by both positive (e.g., SH2B1) and negative (e.g., SOCS3 and PTP1B) regulators and by endoplasmic reticulum stress. Leptin resistance, a primary risk factor for obesity, likely results from impairment in leptin transport, LEPRb signaling, and/or the neurocircuitry of energy balance.

Leptin is secreted into the bloodstream by adipocytes and is required for the maintenance of energy homeostasis and body weight. Leptin deficiency or genetic defects in the components of the leptin signaling pathways causes obesity. Leptin controls energy balance and body weight primarily by targeting LEPRb-expressing neurons in the brain, particularly in the hypothalamus. These LEPRb-expressing neurons function as the first-order neurons that project to the second-order neurons located within and outside the hypothalamus, forming a neural network that controls the energy homeostasis and body weight. Multiple factors, including inflammation and ER stress, contribute to leptin resistance, and leptin resistance is the key risk factor for obesity. This review is focused on recent advance about leptin action, leptin signaling, and leptin resistance.