-The study was designed to evaluate whether changes in malonyl-CoA and the enzymes that govern its concentration occur in human muscle as a result of physical training. Healthy, middle-aged subjects were studied before and after a 12-wk training program that significantly increased V O2 max by 13% and decreased intra-abdominal fat by 17%. Significant decreases (25-30%) in the concentration of malonyl-CoA were observed after training, 24 -36 h after the last bout of exercise. They were accompanied by increases in both the activity (88%) and mRNA (51%) of malonyl-CoA decarboxylase (MCD) in muscle but no changes in the phosphorylation of AMP kinase (AMPK, Thr 172 ) or of acetyl-CoA carboxylase. The abundance of peroxisome proliferator-activated receptor (PPAR)␥ coactivator-1␣ (PGC-1␣), a regulator of transcription that has been linked to the mediation of MCD expression by PPAR␣, was also increased (3-fold). In studies also conducted 24 -36 h after the last bout of exercise, no evidence of increased whole body insulin sensitivity or fatty acid oxidation was observed during an euglycemic hyperinsulinemic clamp. In conclusion, the concentration of malonylCoA is diminished in muscle after physical training, most likely because of PGC-1␣-mediated increases in MCD expression and activity. These changes persist after the increases in AMPK activity and whole body insulin sensitivity and fatty acid oxidation, typically caused by an acute bout of exercise in healthy individuals, have dissipated.insulin sensitivity; adenosine 5Ј-monophosphate kinase; acetyl-coenzyme A carboxylase; peroxisome proliferator-activated receptor-␥ coactivator-1␣ IN MUSCLE, MALONYL-COA allosterically inhibits carnitine palmitoyltransferase (CPT) I and thereby decreases the transfer of long-chain fatty acyl-CoA from the cytosol into mitochondria, where they are oxidized (22). A large body of evidence indicates that the concentration of malonyl-CoA in skeletal muscle responds to acute changes in cellular fuel availability and energy expenditure (EE) (35). Thus increases in malonylCoA have been described in muscle after provision of glucose, such as that which occurs during an euglycemic-hyperinsulinemic clamp (6) or refeeding after a fast (30), whereas decreases in the concentration of malonyl-CoA have been observed in muscle after exercise, which increases fat oxidation (7,9,15,40). Exercise (muscle contraction) lowers the concentration of malonyl-CoA by activating AMP kinase (AMPK), which phosphorylates (Ser 79 ) and inhibits acetyl-CoA carboxylase (ACC), the enzyme that catalyzes the formation of malonyl-CoA from cytosolic acetyl-CoA and CO 2 (7,12,40,49). Studies in animals and humans suggest that sustained elevations of the concentration of malonyl-CoA in skeletal muscle may play a role in the development of insulin resistance (3,20,36). Conversely, decreases in the concentration of malonyl-CoA, caused by an acute bout of exercise (9, 15) or the administration of a single dose of the AMPK activator 5-aminoimidazole-4-carboxamide-1-␤-D-ribofuranos...

Obesity is a prominent feature of the Bardet-Biedl syndrome (BBS), one subset of which, BBS6, is due to mutations in the chaperonin-like gene termed the McKusick-Kaufman syndrome (MKKS) gene. We tested whether variation in MKKS contributes to common and probably polygenic forms of obesity by performing mutation analysis of the coding region in 60 Danish white men with juvenile-onset obesity. Five variants were identified, including two synonymous mutations (Pro(39)Pro and Ile(178)Ile) and three nonsynonymous variants (Ala(242)Ser, Arg(517)Cys, and Gly(532)Val). Furthermore, the rare Ala(242)Ser was identified in two families and showed partial cosegregation with obesity. The Pro(39)Pro, Ile(178)Ile, and Arg(517)Cys variants are in complete linkage disequilibrium and defined a prevalent haplotype. In a case-control study, the Arg(517)Cys polymorphism allele prevalence was 11.4% [95% confidence interval (CI), 9.7-13.0] among 744 men with juvenile-onset obesity and 9.3% (CI, 7.9-10.7) among 867 control subjects (P = 0.048). However, among middle-aged men the allelic prevalence was 9.7% (CI, 7.9-11.4) among 523 obese men and 12.2% (CI, 10.8-13.6) among 1051 lean men (P = 0.037). In conclusion, it is unlikely that MKKS variants play a major role in the pathogenesis of nonsyndromic obesity, although in rare cases the A242S allele may contribute to obesity.

Variations of the small heterodimer partner (SHP, NR0B2) gene, an atypical nuclear receptor that inhibits transactivation by hepatocyte nuclear factor (HNF)-4alpha, are associated with obesity among Japanese. The purpose of the study was to evaluate the prevalence of SHP variants among obese Danish men. Using combined SSCP and heteroduplex analysis, we analyzed the entire coding region of SHP for variants in a cohort of 750 Danish men with early-onset obesity and genotyped a cohort of 795 nonobese control subjects using PCR-RFLP. Functional analyses of the identified coding region variants were performed in both MIN6-m9 and HepG2 cell lines. A total of five novel variants, including three missense variants (c.100C>G [p.R34G], c.278G>A [p.G93D], and c.415C>A [p.P139H]) and two silent variants (c.65C>T [p.Y22Y] and c.339G>A [p.P113P]) were identified. Moreover, the previously reported c.512G>C [p.G171A] polymorphism was identified. The 171A allele was not associated with obesity (p = 0.07). The 34G, 93D, and 139H-alleles were rare variants, which were found only among obese subjects. Among the four coding region variants, the 93D-allele showed a reduced in vitro inhibition of the HNF-4alpha transactivation of the HNF-1alpha promoter expression when expressed in MIN6-m9 and HepG2 cell lines (p<0.01). In contrast to reported findings among obese Japanese, functional variants are rare among Danish men. A functional 93D variant of SHP was identified in 1 out of 750 obese and in none of 795 nonobese control subjects. Further large-scale population studies are necessary to assess the clinical impact of this rare variant on obesity risk among European subjects.

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