Is There a Metabolic Program in the Skeletal Muscle of Obese Individuals?

Severe obesity (BMI ≥ 40 kg/m2) is associated with multiple defects in skeletal muscle which contribute to insulin resistance and a reduction in fatty acid oxidation (FAO) in this tissue. These metabolic derangements are retained in human skeletal muscle cells raised in culture. Together, these findings are indicative of a dysfunctional global metabolic program with severe obesity which is of an epigenetic or genetic origin. Weight loss via gastric bypass surgery can “turn off” and/or correct components of this metabolic program as insulin sensitivity is restored; however, the impairment in FAO in skeletal muscle remains evident. Physical activity can improve FAO and insulin action, indicating that this patient population is not exercise resistant and that exercise offers a pathway to circumvent the abnormal program. Findings presented in this review will hopefully increase the understanding of and aid in preventing and/or treating the severely obese condition

Time course metabolome of Roux-en-Y gastric bypass confirms correlation between leptin, body weight and the microbiome

Roux-en-Y gastric bypass (RYGB) is an effective way to lose weight and reverse type 2 dia- betes. We profiled the metabolome of 18 obese patients (nine euglycemic and nine diabet- ics) that underwent RYGB surgery and seven lean subjects. Plasma samples from the obese patients were collected before the surgery and one week and three months after the surgery. We analyzed the metabolome in association to five hormones (Adiponectin, Insulin, Ghrelin, Leptin, and Resistin), four peptide hormones (GIP, Glucagon, GLP1, and PYY), and two cytokines (IL-6 and TNF). PCA showed samples cluster by surgery time and many microbially driven metabolites (indoles in particular) correlated with the three months after the surgery. Network analysis of metabolites revealed a connection between carbohydrate (mannosamine and glucosamine) and glyoxylate and confirms glyoxylate association to dia- betes. Only leptin and IL-6 had a significant association with the measured metabolites. Lep- tin decreased immediately after RYGB (before significant weight loss), whereas IL-6 showed no consistent response to RYGB. Moreover, leptin associated with tryptophan in support of the possible role of leptin in the regulation of serotonin synthesis pathways in the gut. These results suggest a potential link between gastric leptin and microbial-derived metabolites in the context of obesity and diabetes

Roux-en-Y Gastric Bypass Surgery Regulates Mitochondrial Dynamics Proteins in Primary Human Myotubes Derived from Severely Obese Humans

Mitochondrial dynamics including mitochondrial fission (e.g., Dynamin-related protein 1 (Drp1) and Fission 1 (Fis1)) and fusion (e.g., Mitofusin 2 (MFN 2)) regulates mitochondrial homeostasis. Defects in mitochondrial dynamics are suggested to contribute to skeletal muscle mitochondrial dysfunction and insulin resistance associated with severe obesity. Roux-en-Y gastric bypass (RYGB) surgery markedly improves metabolic health as indicated by enhanced substrate oxidation and insulin action in skeletal muscle. However, the underlying cellular mechanisms responsible for these are unclear and could possibly be due to the improvement of mitochondrial dynamics. PURPOSE: The purpose of this study was to determine whether RYGB surgery improves mitochondria dynamics proteins in primary human myotubes from severely obese humans. METHODS: Primary skeletal muscle cells were isolated from muscle biopsies obtained from six lean subjects (BMI = 23.4 ± 0.6 kg/m2) and six RYGB patients prior to, 1-month and 7-months after surgery (BMI = 50.2 ± 2.0, 43.2 ± 2.8 and 35.7 ± 2.2 kg/m2, respectively) and were differentiated to myotubes. On day 7 of differentiation, myotubes were harvested for further assessing the expressions of mitochondria dynamics proteins. RESULTS: Before surgery, Drp1Ser616 phosphorylation and Fis1 expression were significantly higher in myotubes derived from severely obese patients when compared to lean controls (41% and 26%, respectively, P \u3c 0.05). While there were no improvements at 1-month post-surgery, Drp1Ser616 phosphorylation and Fis1 expression were significantly decreased in myotubes from severely obese humans at 7-months post-surgery (Pre vs. 7-months post: 0.046 ± 0.004 vs. 0.035 ± 0.003; 0.023 ± 0.008 vs. 0.014 ± 0.003 AU; respectively, P \u3c 0.05), and not statistically different from lean controls. However, MFN2 expression did not change post-surgery in comparison to pre-surgery. CONCLUSION: These data suggest that RYGB surgery reduces obesity-induced rise in mitochondrial fission, but not fusion in primary human myotubes derived from severely obese humans

Metformin Improves Insulin Signaling in Obese Rats via Reduced IKK Action in a Fiber-Type Specific Manner

Metformin is a widely used insulin-sensitizing drug, though its mechanisms are not fully understood. Metformin has been shown to activate AMPK in skeletal muscle; however, its effects on the inhibitor of κB kinaseβ (IKKβ) in this same tissue are unknown. The aim of this study was to (1) determine the ability of metformin to attenuate IKKβ action, (2) determine whether changes in AMPK activity are associated with changes in IKKβ action in skeletal muscle, and (3) examine whether changes in AMPK and IKKβ function are consistent with improved insulin signaling. Lean and obese male Zuckers received either vehicle or metformin by oral gavage daily for four weeks (four groups of eight). Proteins were measured in white gastrocnemius (WG), red gastrocnemius (RG), and soleus. AMPK phosphorylation increased (P < .05) in WG in both lean (57%) and obese (106%), and this was supported by an increase in phospho-ACC in WG. Further, metformin increased IκBα levels in both WG (150%) and RG (67%) of obese rats, indicative of reduced IKKβ activity (P < .05), and was associated with reduced IRS1-pSer307 (30%) in the WG of obese rats (P < .02). From these data we conclude that metformin treatment appears to exert an inhibitory influence on skeletal muscle IKKβ activity, as evidenced by elevated IκBα levels and reduced IRS1-Ser307 phosphorylation in a fiber-type specific manner

Is type II diabetes mellitus (NIDDM) a surgical disease?

Since February 1, 1980, 515 morbidly obese patients have undergone the Greenville gastric bypass (GGB) operation. Of these, 212 (41.2%) were euglycemic, 288 (55.9%) were either diabetic or had glucose intolerance, and 15 (2.9%) were unable to complete the evaluation. After the operation, only 30 (5.8%) patients remained diabetic (and 20 of these improved), 457 (88.7%) became and have remained euglycemic, and inadequate data prevented classification of the other 28 (5.4%). The patients who failed to return to normal glucose values were older and their diabetes was of longer duration than those who did. The effect of the GGB was not only limited to the correction of abnormal glucose levels. The GGB also corrected the abnormal levels of fasting insulin and glycosylated hemoglobin in a cohort of 52 consecutive severely obese patients with non-insulin-dependent diabetes. The GGB effectively controls weight. If morbid obesity is defined as 100 pounds over ideal body weight, 89% of the patients are no longer "morbidly" obese within 2 years. In most patients, the control of the weight has been well maintained during the 11 years of follow-up; most of the upward creep in weight of 20.8% between 24 and 132 months was from the 49 (9.5%) patients who had staple line breakdowns between the large and small gastric pouches. Non-insulin-dependent diabetes, previously considered a chronic unrelenting disease, can be controlled in the severely obese by the gastric bypass. Whether the correction of glucose metabolism affects the complications of diabetes is unknown. Whether the gastric bypass should be considered for patients with advanced non-insulin-dependent diabetes but who are not severely obese deserves consideration. The GGB has an unacceptably high rate of staple line failure. Accordingly, the authors have recently changed their procedure to one that divides the stomach rather than partitions it with staples. Originally published Annals of Surgery, Vol. 215, No. 6, June 199

Type 2 Diabetes Modifies Skeletal Muscle Gene Expression Response to Gastric Bypass Surgery

INTRODUCTION: Roux-en-Y gastric bypass (RYGB) is an effective treatment for type 2 diabetes mellitus (T2DM) that can result in remission of clinical symptoms, yet mechanisms for improved skeletal muscle health are poorly understood. We sought to define the impact of existing T2DM on RYGB-induced muscle transcriptome changes. METHODS: Vastus lateralis biopsy transcriptomes were generated pre- and 1-year post-RYGB in black adult females with (T2D; n = 5, age = 51 ± 6 years, BMI = 53.0 ± 5.8 kg/m(2)) and without (CON; n = 7, 43 ± 6 years, 51.0 ± 9.2 kg/m(2)) T2DM. Insulin, glucose, and HOMA-IR were measured in blood at the same time points. ANCOVA detected differentially expressed genes (p < 0.01, fold change < |1.2|), which were used to identify enriched biological pathways. RESULTS: Pre-RYGB, 95 probes were downregulated with T2D including subunits of mitochondrial complex I. Post-RYGB, the T2D group had normalized gene expression when compared to their non-diabetic counterparts with only three probes remaining significantly different. In the T2D, we identified 52 probes upregulated from pre- to post-RYGB, including NDFUB7 and NDFUA1. CONCLUSION: Black females with T2DM show extensive downregulation of genes across aerobic metabolism pathways prior to RYGB, which resolves 1 year post-RYGB and is related to improvements in clinical markers. These data support efficacy of RYGB for improving skeletal muscle health, especially in patients with T2DM

Characterization of a Low Affinity Thyroid Hormone Receptor Binding Site within the Rat GLUT4 Gene Promoter

Previous studies have demonstrated that thyroid hormone (T3) stimulates insulin-responsive glucose transporter (GLUT4) transcription and protein expression in rat skeletal muscle. The aim of the present study was to define a putative thyroid hormone response element (TRE) within the rat GLUT4 promoter and thus perhaps determine whether T3 acts directly to augment skeletal muscle GLUT4 transcription. To this end, electrophoretic mobility shift analyses were performed to analyze thyroid hormone receptor (TR) binding to a previously characterized 281-bp T3-responsive region of the rat GLUT4 promoter. Indeed, within this region, a TR-binding site of the standard DR+4 TRE variety was located between bases −457/−426 and was shown to posses a specific affinity for in vitro translated TRs. Interestingly, however, the GLUT4 TR-binding site demonstrated a significantly lower affinity compared to a consensus DR+4 TRE, and only bound TRs appreciatively in the form of high affinity heterodimers, in this case with the cis-retinoic acid receptor. In conclusion, these data demonstrated the presence of a specific TR-binding site within a T3-responsive region of the rat GLUT4 promoter and thus support the supposition that thyroid hormone acts directly to stimulate GLUT4 transcription in rat skeletal muscle. Moreover, characterization of a novel TR-binding site with low affinity suggests an additional mechanism by which the intrinsic activity and responsiveness of thyroid hormone regulated genes may be modulated