Although white adipocytes are best known as the cell type that sequesters large quantities of neutral lipid, most eukaryotic cells, including skeletal myocytes, form lipid droplets. Current interests in intramyocellular triacylglycerol (IMTG) stem largely from their infamous association with metabolic disease (reviewed in Refs. 1, 2 ). Thus, in the context of obesity and type 2 diabetes, IMTG content Abstract Intramuscular accumulation of triacylglycerol, in the form of lipid droplets (LD), has gained widespread attention as a hallmark of metabolic disease and insulin resistance. Paradoxically, LDs also amass in muscles of highly trained endurance athletes who are exquisitely insulin sensitive. Understanding the molecular mechanisms that mediate the expansion and appropriate metabolic control of LDs in the context of habitual physical activity could lead to new therapeutic opportunities. Herein, we show that acute exercise elicits robust upregulation of a broad program of genes involved in regulating LD assembly, morphology, localization, and mobilization. Prominent among these was perilipin-5, a scaffolding protein that affects the spatial and metabolic interactions between LD and their surrounding mitochondrial reticulum. Studies in transgenic mice and primary human skeletal myocytes established a key role for the exercise-responsive transcriptional coactivator PGC-1 ␣ in coordinating intramuscular LD programming with mitochondrial remodeling. Moreover, translational studies comparing physically active versus inactive humans identifi ed a remarkably strong association between expression of intramuscular LD genes and enhanced insulin action in exercisetrained subjects.These results reveal an intimate molecular connection between intramuscular LD biology and mitochondrial metabolism that could prove relevant to the etiology and treatment of insulin resistance and other disorders of lipid imbalance. Abbreviations: ATGL, adipose triglyceride lipase ; BMI, body mass index; DAG, diacylglycerol; EDL, extensor digitorum longus; EE, energy expenditure; G0S2, G0/G1 switch 2; HF, high fat; HSkMC, human skeletal myotube; IMCL, intramyocellular lipid; IMTG, intramyocellular triacylglycerol; NT, nontransgenic; LD, lipid droplet; PGC-1 ␣ , PPAR ␥ coactivator-1 ␣ ; PLIN5, perilipin family protein 5; PPAR, peroxisome proliferator-activated receptor; Rd, whole-body glucose disposal; ⌬ Rd, change in whole-body glucose disposal (insulin sensitivity); RQ, respiratory quotient; ⌬ RQ, change in respiratory quotient (metabolic fl exibility); SC, standard chow; SCD1, stearoyl-CoA desaturase 1; TA, tibialis anterior; TAG, triacylglycerol; VO 2 max, maximal oxygen consumption per kilogram of body weight as measured during maximal exercise test; Wmax, maximum watts achieved per kilogram of body weight as measured during a maximal exercise test.
Pancreatic islet failure, involving loss of glucose-stimulated insulin secretion (GSIS) from islet β-cells, heralds the onset of type 2 diabetes (T2D). To search for mediators of GSIS, we performed metabolomics profiling of the insulinoma cell line 832/13, and uncovered significant glucose-induced changes in purine pathway intermediates, including a decrease in inosine monophosphate (IMP) and an increase in adenylosuccinate (S-AMP), suggesting a regulatory role for the enzyme that links the two metabolites, adenylosuccinate synthase (ADSS). Inhibition of ADSS or a more proximal enzyme in the S-AMP biosynthesis pathway, adenylosuccinate lyase, lowers S-AMP levels and impairs GSIS. Addition of S-AMP to the interior of patch-clamped human β-cells amplifies exocytosis, an effect dependent upon expression of sentrin/SUMO-specific protease 1 (SENP1). S-AMP also overcomes the defect in glucose-induced exocytosis in β–cells from a human donor with T2D. S-AMP is thus an insulin secretagogue capable of reversing β-cell dysfunction in T2D.
Growth hormone (GH) stimulates lipolysis in mature adipocytes and primary preadipocytes but promotes adipogenesis in preadipocyte cell lines. The lactogenic hormones (prolactin [PRL] and placental lactogen) also stimulate adipogenesis in preadipocyte cell lines but have variable lipolytic and lipogenic effects in mature adipose tissue. We hypothesized that differences in expression of GH receptors (GHR) and PRL receptors (PRLR) during adipocyte development might explain some of the differential effects of the somatogens and lactogens on fat metabolism. To that end, we compared: (a) the expression of GHR and PRLR mRNAs in 3T3-L1 preadipocytes during the course of adipocyte differentiation; (b) the induction of STAT-5 activity by GH and PRL during adipogenesis; and (c) the acute effects of GH and PRL on the suppressors of cytokine signaling (SOCS-1–3 and cytokine-inducible SH2-domain-containing protein [CIS]) and IGF-I. In confluent, undifferentiated 3T3-L1 cells, the levels of GHR mRNA were ∼250-fold higher than the levels of PRLR mRNA. Following induction of adipocyte differentiation the levels of PRLR mRNA rose 90-fold but GHR mRNA increased only 0.8-fold. Expression of both full-length (long) and truncated (short) isoforms of the PRLR increased during differentiation but the long isoform predominated at all time points. Mouse GH (mGH) stimulated increases in STAT-5a and 5b activity in undifferentiated as well as differentiating 3T3-L1 cells; mouse PRL (mPRL) had little or no effect on STAT-5 activity in undifferentiated cells but stimulated increases in STAT-5a and 5b activity in differentiating cells. mGH stimulated increases in SOCS-2 and SOCS-3 mRNAs in undifferentiated cells and SOCS-1–3 and CIS mRNAs in differentiating cells; mPRL induced CIS in differentiating cells but had no effect on SOCS-1–3. mPRL and mGH stimulated increases in IGF-I mRNA in differentiating cells but not in undifferentiated cells; the potency of mGH (3–6-fold increase, p < 0.01) exceeded that of mPRL (40–90% increase, p < 0.05). Our findings reveal disparities in the expression of PRLR and GHR during adipocyte development and differential effects of the hormones on STAT-5, the SOCS proteins, CIS, and IGF-I. These observations suggest that somatogens and lactogens regulate adipocyte development and fat metabolism through distinct but overlapping cellular mechanisms.
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