Whole-body Glucose Metabolism Research Articles

The Role of Hepatic Fat Accumulation in Glucose and Insulin Homeostasis-Dysregulation by the Liver.

Accumulation of hepatic triacylglycerol (TG) is associated with obesity and metabolic syndrome, which are important pathogenic factors in the development of type 2 diabetes. In this narrative review, we summarize the effects of hepatic TG accumulation on hepatic glucose and insulin metabolism and the underlying molecular regulation in order to highlight the importance of hepatic TG accumulation for whole-body glucose metabolism. We find that liver fat accumulation is closely linked to impaired insulin-mediated suppression of hepatic glucose production and reduced hepatic insulin clearance. The resulting systemic hyperinsulinemia has a major impact on whole-body glucose metabolism and may be an important pathogenic step in the development of type 2 diabetes.

Exercise intensity regulates cytokine and klotho responses in men

BackgroundShort-term exercise training programs that consist of moderate intensity endurance training or high intensity interval training have become popular choices for healthy lifestyle modifications, with as little as two weeks of training being shown to improve cardiorespiratory fitness and whole-body glucose metabolism. An emerging concept in exercise biology is that exercise stimulates the release of cytokines and other factors into the blood that contribute to the beneficial effects of exercise on metabolism, but whether these factors behave similarly in response to moderate and high intensity short term training is not known. Here, we determined the effects of two short-term exercise training programs on the concentrations of select secreted cytokines and Klotho, a protein involved in anti-aging.MethodsHealthy, sedentary men (n = 22) were randomized to moderate intensity training (MIT) or sprint intensity training (SIT) treatment groups. SIT consisted of 6 sessions over 2 weeks of 6 × 30 s all out cycle ergometer sprints with 4 min of recovery between sprints. MIT consisted of 6 sessions over 2 weeks of cycle ergometer exercise at 60% VO2peak, gradually increasing in duration from 40 to 60 min. Blood was taken before the intervention and 48 h after the last training session, and glucose uptake was measured using [18F]FDG‐PET/CT scanning. Cytokines were measured by multiplex and Klotho concentrations by ELISA.ResultsBoth training protocols similarly increased VO2peak and decreased fat percentage and visceral fat (P < 0.05). MIT and SIT training programs both reduced the concentrations of IL-6, Hepatocyte Growth Factor (HGF) and Leptin. Interestingly, MIT, but not SIT increased monocyte chemoattractant protein-1 (MCP-1) concentrations, an exercise-induced cytokine, as well as Klotho concentrations.ConclusionShort-term exercise training at markedly different intensities similarly improves cardiovascular fitness but results in intensity-specific changes in cytokine responses to exercise.

Intercellular Transmission of Hepatic ER Stress in Obesity Disrupts Systemic Metabolism

Endoplasmic reticulum stress (ERS) has a pathophysiological role in obesity-associated insulin resistance. Yet, the coordinated tissue response to ERS remains unclear. Increased connexin 43 (Cx43)-mediated intercellular communication has been implicated in tissue-adaptive and -maladaptive response to various chronic stresses. Here, we demonstrate that in hepatocytes, ERS results in increased Cx43 expression and cell-cell coupling. Co-culture of ER-stressed "donor" cells resulted in intercellular transmission of ERS and dysfunction to ERS-naive "recipient" cells ("bystander response"), which could be prevented by genetic or pharmacologic suppression of Cx43. Hepatocytes from obese mice were able to transmit ERS to hepatocytes from lean mice, and mice lacking liver Cx43 were protected from diet-induced ERS, insulin resistance, and hepatosteatosis. Taken together, our results indicate that in obesity, the increased Cx43-mediated cell-cell coupling allows intercellular propagation of ERS. This novel maladaptive response to over-nutrition exacerbates the tissue ERS burden, promoting hepatosteatosis and impairing whole-body glucose metabolism.

Effect of maternal nutrient restriction on expression of glucose transporters (SLC2A4 and SLC2A1) and insulin signaling in skeletal muscle of SGA and Non-SGA sheep fetuses

Maternal nutrient restriction (NR) causes small for gestational age (SGA) offspring, which are at higher risk for accelerated postnatal growth and developing insulin resistance in adulthood. Skeletal muscle is essential for whole-body glucose metabolism, as 80% of insulin-mediated glucose uptake occurs in this tissue. Maternal NR can alter fetal skeletal muscle mass, expression of glucose transporters, insulin signaling, and myofiber type composition. It also leads to accumulation of intramuscular triglycerides (IMTG), which correlates to insulin resistance. Using a 50% NR treatment from gestational day (GD) 35 to GD 135 in sheep, we routinely observe a spectral phenotype of fetal weights within the NR group. Thus, we classified those fetuses into NR(Non-SGA; n = 11) and NR(SGA; n = 11). The control group (n = 12) received 100% of nutrient requirements throughout pregnancy. At GD 135, fetal plasma and gastrocnemius and soleus muscles were collected. In fetal plasma, total insulin was lower in NR(SGA) fetuses compared NR(Non-SGA) and control fetuses (P < 0.01), whereas total IGF-1 was lower in NR(SGA) fetuses compared with control fetuses (P < 0.05). Within gastrocnemius, protein expression of insulin receptor (INSRB; P < 0.05) and the glucose transporters, solute carrier family 2 member 1 and solute carrier family 2 member 4, was higher (P < 0.05) in NR(SGA) fetuses compared with NR(Non-SGA) fetuses; IGF-1 receptor protein was increased (P < 0.01) in NR(SGA) fetuses compared with control fetuses, and a lower (P < 0.01) proportion of type I myofibers (insulin sensitive and oxidative) was observed in SGA fetuses. For gastrocnemius muscle, the expression of lipoprotein lipase (LPL) messenger RNA (mRNA) was upregulated (P < 0.05) in both NR(SGA) and NR(Non-SGA) fetuses compared with control fetuses, whereas carnitine palmitoyltransferase 1B (CPT1B) mRNA was higher (P < 0.05) in NR(Non-SGA) fetuses compared with control fetuses, but there were no differences (P > 0.05) for protein levels of LPL or CPT1B. Within soleus, there were no differences (P > 0.05) for any characteristic except for the proportion of type I myofibers, which was lower (P < 0.05) in NR(SGA) fetuses compared with control fetuses. Accumulation of IMTG did not differ (P > 0.05) in gastrocnemius or soleus muscles. Collectively, the results indicate molecular differences between SGA and Non-SGA fetuses for most characteristics, suggesting that maternal NR induces a spectral phenotype for the metabolic programming of those fetuses.

Are Alterations in Skeletal Muscle Mitochondria a Cause or Consequence of Insulin Resistance?

As a major site of glucose uptake following a meal, skeletal muscle has an important role in whole-body glucose metabolism. Evidence in humans and animal models of insulin resistance and type 2 diabetes suggests that alterations in mitochondrial characteristics accompany the development of skeletal muscle insulin resistance. However, it is unclear whether changes in mitochondrial content, respiratory function, or substrate oxidation are central to the development of insulin resistance or occur in response to insulin resistance. Thus, this review will aim to evaluate the apparent conflicting information placing mitochondria as a key organelle in the development of insulin resistance in skeletal muscle.

Hepatic insulin-degrading enzyme regulates glucose and insulin homeostasis in diet-induced obese mice

The insulin-degrading enzyme (IDE) is a metalloendopeptidase with a high affinity for insulin. Human genetic polymorphisms in Ide have been linked to increased risk for T2DM. In mice, hepatic Ide ablation causes glucose intolerance and insulin resistance when mice are fed a regular diet. ObjectiveThese studies were undertaken to further investigate its regulatory role in glucose homeostasis and insulin sensitivity in diet-induced obesity. MethodsTo this end, we have compared the metabolic effects of loss versus gain of IDE function in mice fed a high-fat diet (HFD). ResultsWe demonstrate that loss of IDE function in liver (L-IDE-KO mouse) exacerbates hyperinsulinemia and insulin resistance without changes in insulin clearance but in parallel to an increase in pancreatic β-cell function. Insulin resistance was associated with increased FoxO1 activation and a ~2-fold increase of GLUT2 protein levels in the liver of HFD-fed mice in response to an intraperitoneal injection of insulin. Conversely, gain of IDE function (adenoviral delivery) improves glucose tolerance and insulin sensitivity, in parallel to a reciprocal ~2-fold reduction in hepatic GLUT2 protein levels. Furthermore, in response to insulin, IDE co-immunoprecipitates with the insulin receptor in liver lysates of mice with adenoviral-mediated liver overexpression of IDE. ConclusionsWe conclude that IDE regulates hepatic insulin action and whole-body glucose metabolism in diet-induced obesity via insulin receptor levels.

Exercise-Induced Improvements to Whole Body Glucose Metabolism in Type 2 Diabetes: The Essential Role of the Liver.

Type 2 diabetes (T2D) is a metabolic disease characterized by obesity, insulin resistance, and the dysfunction of several key glucoregulatory organs. Among these organs, impaired liver function is recognized as one of the earliest contributors to impaired whole-body glucose homeostasis, with well-characterized hepatic insulin resistance resulting in elevated rates of hepatic glucose production (HGP) and fasting hyperglycemia. One portion of this review will provide an overview of how HGP is regulated during the fasted state in healthy humans and how this process becomes dysregulated in patients with T2D. Less well-appreciated is the liver's role in post-prandial glucose metabolism, where it takes up and metabolizes one-third of orally ingested glucose. An abundance of literature has shown that the process of hepatic glucose uptake is impaired in patients with T2D, thereby contributing to glucose intolerance. A second portion of this review will outline how hepatic glucose uptake is regulated during the post-prandial state, and how it becomes dysfunctional in patients with T2D. Finally, it is well-known that exercise training has an insulin-sensitizing effect on the liver, which contributes to improved whole-body glucose metabolism in patients with T2D, thereby making it a cornerstone in the management of the disease. To this end, the impact of exercise on hepatic glucose metabolism will be thoroughly discussed, referencing key findings in the literature. At the same time, sources of heterogeneity that contribute to inconsistent findings in the field will be pointed out, as will important topics for future investigation.

Influenza infection rewires energy metabolism and induces browning features in adipose cells and tissues

Like all obligate intracellular pathogens, influenza A virus (IAV) reprograms host cell’s glucose and lipid metabolism to promote its own replication. However, the impact of influenza infection on white adipose tissue (WAT), a key tissue in the control of systemic energy homeostasis, has not been yet characterized. Here, we show that influenza infection induces alterations in whole-body glucose metabolism that persist long after the virus has been cleared. We report depot-specific changes in the WAT of IAV-infected mice, notably characterized by the appearance of thermogenic brown-like adipocytes within the subcutaneous fat depot. Importantly, viral RNA- and viral antigen-harboring cells are detected in the WAT of infected mice. Using in vitro approaches, we find that IAV infection enhances the expression of brown-adipogenesis-related genes in preadipocytes. Overall, our findings shed light on the role that the white adipose tissue, which lies at the crossroads of nutrition, metabolism and immunity, may play in influenza infection.

The role of brown adipose tissue and the thermogenic adipocytes in glucose metabolism: recent advances and open questions.

Brown adipose tissue (BAT) and the thermogenic adipocytes in white adipose tissue (WAT) are considered emerging targets against obesity-related metabolic perturbations given their high capacity for thermogenesis and glucose and lipid disposal. This manuscript summarizes and critically evaluates the recent advances on the role of BAT and thermogenic adipocytes in glucose homeostasis in humans. Recent studies support that BAT has high capacity for glucose disposal not only during cold but during rewarming and thermoneutrality as well. Moreover, BAT is now considered a metabolic sink for the disposal of branched-chain amino acids improving whole-body glucose metabolism in rodents and, potentially, in humans. β3 adrenergic agonism and glucagon-like peptide 1 increase BAT metabolic activity for glucose and/or induce the browning of WAT. Finally, recent findings support the association of glucose disposal in BAT with subclinical atherosclerosis and the reproducibility of two advanced medical imaging methods for the assessment of BAT using a glucose radiotracer. Recent studies provide new insights on the role of human BAT and thermogenic adipocytes in glucose metabolism. However, further research is needed to unequivocally establish the clinical significance of BAT and the thermogenic adipocytes in glucose homeostasis in humans.

In Vitro, In Vivo, and In Silico Methods for Assessment of Muscle Size and Muscle Growth Regulation.

ABSTRACTTrauma, burn injury, sepsis, and ischemia lead to acute and chronic loss of skeletal muscle mass and function. Healthy muscle is essential for eating, posture, respiration, reproduction, and mobility, as well as for appropriate function of the senses including taste, vision, and hearing. Beyond providing support and contraction, skeletal muscle also exerts essential roles in temperature regulation, metabolism, and overall health. As the primary reservoir for amino acids, skeletal muscle regulates whole-body protein and glucose metabolism by providing substrate for protein synthesis and supporting hepatic gluconeogenesis during illness and starvation. Overall, greater muscle mass is linked to greater insulin sensitivity and glucose disposal, strength, power, and longevity. In contrast, low muscle mass correlates with dysmetabolism, dysmobility, and poor survival. Muscle mass is highly plastic, appropriate to its role as reservoir, and subject to striking genetic control. Defining mechanisms of muscle growth regulation holds significant promise to find interventions that promote health and diminish morbidity and mortality after trauma, sepsis, inflammation, and other systemic insults. In this invited review, we summarize techniques and methods to assess and manipulate muscle size and muscle mass in experimental systems, including cell culture and rodent models. These approaches have utility for studies of myopenia, sarcopenia, cachexia, and acute muscle growth or atrophy in the setting of health or injury.

Glucose and protein metabolic responses to an energy- but not protein- restricted diet in type 2 diabetes.

To test the effect of energy restriction with maintained protein intake on body composition and on insulin sensitivity of glucose and protein metabolism in adults with type 2 diabetes (T2D). After 3 days of an isoenergetic diet with 1.2 g/kg/d protein, obese adults with T2D (three women, two men) followed a 5-week diet providing 60% of energy requirements with 45% carbohydrate, and with protein maintained at pre-intervention level. Isotopic tracers were used to quantify whole-body glucose (3-3 H-glucose) and protein (13 C-leucine) metabolism pre- (day 4) and post-intervention (day 39), in the postabsorptive state and during a hyperinsulinaemic, isoglycaemic, isoaminoacidaemic clamp. Body composition was measured using dual-energy x-ray absorptiometry. After energy restriction, 6% weight loss occurred via total body (11%) and visceral fat losses (25%), but lean mass was preserved. Fasting glucose level, serum insulin level, homeostatic model assessment of insulin resistance index and C-peptide level decreased significantly (29%, 38%, 54% and 38%, respectively) as did other cardiometabolic risk factors. Between clamp studies, postabsorptive protein turnover and oxidation rates decreased (12% and 32%), resulting in less negative net balance, consistent with protein conservation. The rates of glucose turnover decreased, and glucose metabolic clearance rate improved (24%). During the clamp, protein flux was lower (9%) and breakdown suppressed (12%), and net balance became less negative but not different. Although glucose turnover did not differ, metabolic clearance improved by 47%. In obese adults with T2D, an energy-restricted diet with maintained protein intake of ~1.2 g/kg/d improved the kinetics of protein metabolism (particularly in the postabsorptive state), and preserved lean body mass and increased glucose metabolic clearance rate.

WWP1 knockout in mice exacerbates obesity-related phenotypes in white adipose tissue but improves whole-body glucose metabolism.

White adipose tissue (WAT) is important for maintenance of homeostasis, because it stores energy and secretes adipokines. The WAT of obese people demonstrates mitochondrial dysfunction, accompanied by oxidative stress, which leads to insulin resistance. WW domain‐containing E3 ubiquitin protein ligase 1 (WWP1) is a member of the HECT‐type E3 family of ubiquitin ligases and is associated with several diseases. Recently, we demonstrated that WWP1 is induced specifically in the WAT of obese mice, where it protects against oxidative stress. Here, we investigated the function of WWP1 in WAT of obese mice by analyzing the phenotype of Wwp1 knockout (KO) mice fed a high‐fat diet. The levels of oxidative stress markers were higher in obese WAT from Wwp1 KO mice. Moreover, Wwp1 KO mice had lower activity of citrate synthase, a mitochondrial enzyme. We also measured AKT phosphorylation in obese WAT and found lower levels in Wwp1 KO mice. However, plasma insulin level was low and glucose level was unchanged in obese Wwp1 KO mice. Moreover, both glucose tolerance test and insulin tolerance test were improved in obese Wwp1 KO mice. These findings indicate that WWP1 participates in the antioxidative response and mitochondrial function in WAT, but knockdown of WWP1 improves whole‐body glucose metabolism.

Nicotinamide riboside supplementation to improve skeletal muscle mitochondrial health and whole-body glucose homeostasis: does it actually work in humans?

Nicotinamide riboside supplementation to improve skeletal muscle mitochondrial health and whole-body glucose homeostasis: does it actually work in humans?

A siRNA mediated hepatic dpp4 knockdown affects lipid, but not glucose metabolism in diabetic mice.

Systemic inhibition of dipeptidyl peptidase 4 (dpp4) represents an effective and established treatment option for type 2 diabetes (T2D). The current study investigated in mice if a liver selective knock-down of dpp4 by therapeutic siRNAs could be a novel, similarly effective treatment option for T2D. Furthermore, the potential effects on hepatic steatosis, inflammation and lipid metabolism were investigated after hepato-selective knock-down of dpp4. The knock-down efficiency and IC50 values of siRNAs targeting dpp4 were analyzed in PC3 cells. In two independent studies, either db/db mice or C57BL/6J mice were injected intravenously with a liposomal formulation of siRNAs targeting either dpp4 or a non-targeting control, followed by metabolically characterization. In comparator groups, additional cohorts of mice were treated with an oral dpp4 inhibitor. In both animal studies, we observed a robust knock-down (~75%) of hepatic dpp4 with a potent siRNA. Hepatic dpp4 knockdown did not significantly affect glucose metabolism or circulating incretin concentrations in both animal studies. However, in obese and diabetic db/db mice hepatic steatosis was reduced and hepatic mRNA expression of acaca, scd1, fasn and pparg was significantly lower after siRNA treatment. Systemic inhibition of the enzymatic dpp4 activity by an oral dpp4 inhibitor significantly improved glucose handling in db/db mice but did not affect hepatic endpoints. These data demonstrate that a targeted reduction of dpp4 expression in the liver may not be sufficient to improve whole-body glucose metabolism in obese and diabetic mice but may improve hepatic lipid metabolism.

Short-term interleukin-37 treatment improves vascular endothelial function, endurance exercise capacity, and whole-body glucose metabolism in old mice.

Aging is associated with vascular endothelial dysfunction, reduced exercise tolerance, and impaired whole‐body glucose metabolism. Interleukin‐37 (IL‐37), an anti‐inflammatory cytokine of the interleukin‐1 family, exerts salutary physiological effects in young mice independent of its inflammation‐suppressing properties. Here, we assess the efficacy of IL‐37 treatment for improving physiological function in older age. Old mice (26–28 months) received daily intraperitoneal injections of recombinant human IL‐37 (recIL‐37; 1 µg/200 ml PBS) or vehicle (200 ml PBS) for 10–14 days. Vascular endothelial function (ex vivo carotid artery dilation to increasing doses of acetylcholine, ACh) was enhanced in recIL‐37 vs. vehicle‐treated mice via increased nitric oxide (NO) bioavailability (all p < .05); this effect was accompanied by enhanced ACh‐stimulated NO production and reduced levels of reactive oxygen species in endothelial cells cultured with plasma from IL‐37‐treated animals (p < .05 vs. vehicle plasma). RecIL‐37 treatment increased endurance exercise capacity by 2.4‐fold, which was accompanied by a 2.9‐fold increase in the phosphorylated AMP‐activated kinase (AMPK) to AMPK ratio (i.e., AMPK activation) in quadriceps muscle. RecIL‐37 treatment also improved whole‐body insulin sensitivity and glucose tolerance (p < .05 vs. vehicle). Improvements in physiological function occurred without significant changes in plasma, aortic, and skeletal muscle pro‐inflammatory proteins (under resting conditions), whereas pro‐/anti‐inflammatory IL‐6 was greater in recIL‐37‐treated animals. Plasma metabolomics analysis revealed that recIL‐37 treatment altered metabolites related to pathways involved in NO synthesis (e.g., increased L‐arginine and citrulline/arginine ratio) and fatty acid metabolism (e.g., increased pantothenol and free fatty acids). Our findings provide experimental support for IL‐37 therapy as a novel strategy to improve diverse physiological functions in old age.

Interleukin-4 Promotes Myogenesis and Boosts Myocyte Insulin Efficacy.

Anti-inflammatory cytokine interleukin-4 (IL-4) promotes glucose tolerance and insulin sensitivity while reduces lipid deposits. However, the effects of IL-4 on energy metabolism in muscle, the largest insulin-targeting organ, remain obscure. The study aimed at addressing the roles of IL-4 in myocyte differentiation (myogenesis) and energy metabolism of muscle cells. Effects of IL-4 on myogenesis, and interaction between IL-4 and insulin on glucose metabolism of C2C12 myoblasts and the terminal differentiated myocytes were analyzed. IL-4 improved GLUT4 translocation and tended to elevate glucose uptake by boosting insulin signaling. In diabetic mice, transient and long-term IL-4 showed differential effects on insulin signaling and efficacy. The study provides evidence to address the roles of IL-4 in mediating whole-body muscle reservoir and glucose metabolism, as well as the interaction between immune responses and energy homeostasis. IL-4 has dual potential to act as an adjuvant therapeutic target for sarcopenia to preserve muscle mass and insulin resistance to improve insulin sensitivity, which implicates the regulation of immune system to the muscle differentiation and exercise performance.

Roux-en-Y gastric bypass surgery improves hepatic glucose metabolism and reduces plasma kisspeptin levels in morbidly obese patients with type 2 diabetes.

Roux-en-Y gastric bypass surgery (RYGB) is known to improve whole-body glucose metabolism in patients with type 2 diabetes (T2D), although the mechanisms are not entirely clear and are likely multifactorial. The aim of this study was to assess fasting hepatic glucose metabolism and other markers of metabolic activity before and after RYGB in patients with and without T2D. Methods: Metabolic characteristics of patients who are obese with T2D were compared with those without the disease (non-T2D) before and 1 and 6 mo after RYGB. Fasting plasma insulin and the insulin:glucagon ratio were markedly reduced as early as 1 mo after RYGB in both patients with T2D and without T2D. Despite this reduction, endogenous glucose production and fasting plasma glucose levels were lower in both groups after RYGB, with the reductions being much larger in T2D. Plasma kisspeptin, an inhibitor of insulin secretion, was reduced only in T2D after surgery. Improved hepatic glucose metabolism and lower plasma kisspeptin in T2D after RYGB may link improved hepatic function with enhanced insulin responsiveness after surgery.NEW & NOTEWORTHY Our manuscript is the first, to the best of our knowledge, to present data showing that Roux-en-Y gastric bypass surgery (RYGB) lowers fasting kisspeptin levels in patients who are obese with type 2 diabetes. This lowering of kisspeptin is important because it could link improvements in liver glucose metabolism after RYGB with increased insulin responsiveness also seen after surgery.

Metabolic effects of skeletal muscle-specific deletion of beta-arrestin-1 and -2 in mice.

Type 2 diabetes (T2D) has become a major health problem worldwide. Skeletal muscle (SKM) is the key tissue for whole-body glucose disposal and utilization. New drugs aimed at improving insulin sensitivity of SKM would greatly expand available therapeutic options. β-arrestin-1 and -2 (Barr1 and Barr2, respectively) are two intracellular proteins best known for their ability to mediate the desensitization and internalization of G protein-coupled receptors (GPCRs). Recent studies suggest that Barr1 and Barr2 regulate several important metabolic functions including insulin release and hepatic glucose production. Since SKM expresses many GPCRs, including the metabolically important β2-adrenergic receptor, the goal of this study was to examine the potential roles of Barr1 and Barr2 in regulating SKM and whole-body glucose metabolism. Using SKM-specific knockout (KO) mouse lines, we showed that the loss of SKM Barr2, but not of SKM Barr1, resulted in mild improvements in glucose tolerance in diet-induced obese mice. SKM-specific Barr1- and Barr2-KO mice did not show any significant differences in exercise performance. However, lack of SKM Barr2 led to increased glycogen breakdown following a treadmill exercise challenge. Interestingly, mice that lacked both Barr1 and Barr2 in SKM showed no significant metabolic phenotypes. Thus, somewhat surprisingly, our data indicate that SKM β-arrestins play only rather subtle roles (SKM Barr2) in regulating whole-body glucose homeostasis and SKM insulin sensitivity.

Mss51 deletion enhances muscle metabolism and glucose homeostasis in mice.

Myostatin is a negative regulator of muscle growth and metabolism and its inhibition in mice improves insulin sensitivity, increases glucose uptake into skeletal muscle, and decreases total body fat. A recently described mammalian protein called MSS51 is significantly downregulated with myostatin inhibition. In vitro disruption of Mss51 results in increased levels of ATP, β-oxidation, glycolysis, and oxidative phosphorylation. To determine the in vivo biological function of Mss51 in mice, we disrupted the Mss51 gene by CRISPR/Cas9 and found that Mss51-KO mice have normal muscle weights and fiber-type distribution but reduced fat pads. Myofibers isolated from Mss51-KO mice showed an increased oxygen consumption rate compared with WT controls, indicating an accelerated rate of skeletal muscle metabolism. The expression of genes related to oxidative phosphorylation and fatty acid β-oxidation were enhanced in skeletal muscle of Mss51-KO mice compared with that of WT mice. We found that mice lacking Mss51 and challenged with a high-fat diet were resistant to diet-induced weight gain, had increased whole-body glucose turnover and glycolysis rate, and increased systemic insulin sensitivity and fatty acid β-oxidation. These findings demonstrate that MSS51 modulates skeletal muscle mitochondrial respiration and regulates whole-body glucose and fatty acid metabolism, making it a potential target for obesity and diabetes.

Overproduction of inter-α-trypsin inhibitor heavy chain 1 after loss of Gα13 in liver exacerbates systemic insulin resistance in mice.

The impact of liver disease on whole-body glucose homeostasis is largely attributed to dysregulated release of secretory proteins in response to metabolic stress. The molecular cues linking liver to whole-body glucose metabolism remain elusive. We found that expression of G protein α-13 (Gα13) was decreased in the liver of mice and humans with diabetes. Liver-specific deletion of the Gna13 gene in mice resulted in systemic glucose intolerance. Comparative secretome analysis identified inter-α-trypsin inhibitor heavy chain 1 (ITIH1) as a protein secreted by liver that was responsible for systemic insulin resistance in Gna13-deficient mice. Liver expression of ITIH1 positively correlated with surrogate markers for diabetes in patients with impaired glucose tolerance or overt diabetes. Mechanistically, a decrease in hepatic Gα13 caused ITIH1 oversecretion by liver through induction of O-GlcNAc transferase expression, facilitating ITIH1 deposition on the hyaluronan surrounding mouse adipose tissue and skeletal muscle. Neutralization of secreted ITIH1 ameliorated glucose intolerance in obese mice. Our findings demonstrate systemic insulin resistance in mice resulting from liver-secreted ITIH1 downstream of Gα13 and its reversal by ITIH1 neutralization.