Biomedical subjects

F Andreelli

Publications and source records attributed to F Andreelli.

At least 19 recordsLinked to original sources

PubMed2005

[How to manage the metabolic syndrome?].

The metabolic syndrome represents the association in a single individual of a cluster of metabolic and hemodynamic factors, leading to an increased risk of type 2 diabetes and/or cardiovascular diseases. Several definitions exist (WHO, EGIR, NCEP-ATP III, AACE), but all of them include a cluster of criteria (hyper glycemia or type 2 diabetes, arterial hypertension, dyslipidemia, abdominal obesity) which increased these risks in parallel to their aggregation. The prevalence of the metabolic syndrome in industrialized countries represents 10 to 30% of the adult population, depending on the definition used and of the range of age, with a regular progression, particularly in women. Thus, it is needed to identify subjects with metabolic syndrome in the general population, and not only in overweight/obese subjects. This review, briefly presents the main definitions, as well as current data on pathophysiology, prevalence and consequences of the metabolic syndrome. Steps to diagnose it and guidance for the therapeutic management of metabolic syndrome in primary care practice are described.

Humans↗

PubMed2003

What kind of simple fasting index should be used to estimate insulin sensitivity in humans?

The hyperinsulinemic euglycemic glucose clamp method is the gold standard for measuring insulin resistance. However it is complex, and simple indexes have been developed. Some of them are based on formulae that calculate the product or the addition of fasting plasma insulin and glucose values whereas others are based on their ratios. We calculated several simple indexes of insulin resistance and compared them to hyperinsulinemic euglycemic clamp data in 111 subjects with a wide range of insulin resistance. We showed that indexes using insulin and glucose ratios in their formulae are poorly correlated with clamp measurements and give false evaluations, particularly in glucose-intolerant and type 2 diabetic subjects. Thus, whatever the glucose profile of study subjects, we suggest the use of a simple index based on the product or the addition of fasting plasma insulin and glucose values instead of their ratios to obtain insulin resistance evaluations close to the hyperinsulinemic euglycemic clamp technique.

Blood Glucose↗

PubMed2003

A possible role for AMP-activated protein kinase in exercise-induced glucose utilization: insights from humans and transgenic animals.

Exercise-induced glucose uptake in skeletal muscle is mediated by an insulin-independent mechanism, but the actual signals to glucose transport in response to muscle contraction have not been identified. The 5'-AMP-activated protein kinase (AMPK) has emerged as a putative mediator of contraction-induced glucose transport, although no conclusive evidence has been provided so far. Recent experiments in AMPK transgenic mice suggest that glucose transport induced by 5-amino-4-imidazolecarboxamide riboside (AICAR) or hypoxia is mediated by AMPK. In contrast, contraction-induced glucose transport in rodent skeletal muscle induced by electrical stimulation in vitro or in situ is not influenced or is only partially reduced by abolishing both or one of the catalytic AMPK subunits. This is compatible with exercise studies done in humans, where no tight correlation is found between AMPK activity and glucose uptake during exercise. Taken together, these results question an essential role of AMPK in exercise-induced glucose uptake and imply that one or more additional pathways are involved in mediating glucose transport in skeletal muscle during exercise.

AMP-Activated Protein Kinases↗

PubMed2003

Physiological role of AMP-activated protein kinase (AMPK): insights from knockout mouse models.

AMP-activated protein kinase (AMPK) is viewed as a fuel sensor for glucose and lipid metabolism. To understand better the physiological role of the catalytic AMPK subunit isoforms, we generated two knockout mouse models with the alpha1 (AMPK alpha 1(-/-)) and alpha 2 (AMPK alpha 2(-/-)) catalytic subunit genes deleted. No defect in glucose homoeostasis was observed in AMPK alpha 1(-/-) mice. On the other hand, AMPK alpha 2(-/-) mice presented high plasma glucose levels and low plasma insulin concentrations in the fed period and during the glucose tolerance test. Nevertheless, in isolated AMPK alpha 2(-/-) pancreatic islets, glucose-stimulated insulin secretion was not affected. Surprisingly, AMPK alpha 2(-/-) mice were insulin-resistant and had reduced muscle glycogen synthesis as assessed in vivo by the hyperinsulinaemic euglycaemic clamp procedure. Reduction of insulin sensitivity and glycogen synthesis were not dependent on the lack of AMPK in skeletal muscle, since mice expressing a dominant inhibitory mutant of AMPK in skeletal muscle were not affected and since insulin-stimulated glucose transport in incubated muscles in vitro was normal in AMPK alpha 2(-/-) muscles. Furthermore, AMPK alpha 2(-/-) mice have a higher sympathetic tone, as shown by increased catecholamine urinary excretion. Increased adrenergic tone could explain both decreased insulin secretion and insulin resistance observed in vivo in AMPK alpha 2(-/-) mice. We suggest that the alpha2 catalytic subunit of AMPK plays a major role as a fuel sensor by modulating the activity of the autonomous nervous system in vivo.

AMP-Activated Protein Kinases↗

PubMed2002

[Total pancreatectomy for mucinous pancreatic tumor].

AIM OF THE STUDY: To report our experience of total pancreatectomy (TP) in ten patients with mucinous pancreatic tumors (MPT), to discuss pre and peroperative investigations in the management of MPT, and operative, functional and carcinologic results after TP. PATIENTS AND METHODS: This retrospective study from January 1985 to January 2001 included ten patients, 5 men and 5 women (mean aged: 64 years). Six patients underwent one step TP for intraductal papillary mucinous tumor of the pancreas (IPMT) in 5 cases, and multifocal mucinous cystadenoma in one case. Four patients underwent a second step TP for tumor recurrence (2 IPMT, and 2 cystadenocarcinomas) which occurred 12 to 121 months post operatively (mean: 49 months). RESULTS: Post TP diabetes was controlled by insulinotherapy (3 injections a day), except in one patient who needed insulin administration through a pump. One patient, with cystadenocarcinoma, died from cancer recurrence 18 months after TP and 140 months after the initial pancreaticoduodenectomy. One patient died from heart disease 34 months postoperatively. The 8 other patients were alive with a mean follow-up of 33 months (range 11-61 months). CONCLUSION: Curative surgery for mucinous tumors of the pancreas may require TP, which is indicated preoperatively according to imaging, or intraoperatively following surgical findings and frozen section of the pancreatic margin. Totalization of a previous partial pancreatectomy is mandatory in case of tumoral persistence or recurrence in the pancreatic remnant. Postoperative diabetes can be managed successfully by a specialized team.

Adenocarcinoma, Mucinous↗

PubMed2001

Regulation by insulin of gene expression in human skeletal muscle and adipose tissue. Evidence for specific defects in type 2 diabetes.

Defective regulation of gene expression may be involved in the pathogenesis of type 2 diabetes. We have characterized the concerted regulation by insulin (3-h hyperinsulinemic clamp) of the expression of 10 genes related to insulin action in skeletal muscle and in subcutaneous adipose tissue, and we have verified whether a defective regulation of some of them could be specifically encountered in tissues of type 2 diabetic patients. Basal mRNA levels (determined by reverse transcriptase-competitive polymerase chain reaction) of insulin receptor, insulin receptor substrate-1, p85alpha phosphatidylinositol 3-kinase (PI3K), p110alphaPI3K, p110betaPI3K, GLUT4, glycogen synthase, and sterol regulatory-element-binding protein-1c (SREBP-1c) were similar in muscle of control (n = 17), type 2 diabetic (n = 9), type 1 diabetic (n = 9), and nondiabetic obese (n = 9) subjects. In muscle, the expression of hexokinase II was decreased in type 2 diabetic patients (P < 0.01). In adipose tissue, SREBP-1c (P < 0.01) mRNA expression was reduced in obese (nondiabetic and type 2 diabetic) subjects and was negatively correlated with the BMI of the subjects (r = -0.63, P = 0.02). Insulin (+/-1,000 pmol/l) induced a two- to threefold increase (P < 0.05) in hexokinase II, p85alphaPI3K, and SREBP-1c mRNA levels in muscle and in adipose tissue in control subjects, in insulin-resistant nondiabetic obese patients, and in hyperglycemic type 1 diabetic subjects. Upregulation of these genes was completely blunted in type 2 diabetic patients. This study thus provides evidence for a specific defect in the regulation of a group of important genes in response to insulin in peripheral tissues of type 2 diabetic patients.

Adipose Tissue↗

PubMed2001

Metformin retention independent of renal failure in intestinal occlusion.

Metformin is eliminated by the kidneys, and metformin accumulation has always been noticed in oligo-anuric patients. We have reported an exception to the rule with the case of a metformin-treated patient having metformin accumulation contrasting with a mild increase in serum creatinine in the context of a volvulus of the sigmoid colon. This case prompted us to examine the association between intestinal occlusion and plasma metformin concentrations. For this purpose, we developed an experimental animal model of mechanical obstruction of the intestine. Rats were pre-treated during 3 weeks via drinking solution at a dose of approximately 100 mg/kg/day of metformin. They underwent at day 0 either sham-operation (n=7) or operation (n=8) to place a plastic tube around the ileum near the ileocaecal valve. Metformin administration was pursued on days 1, 2, and 3 giving a single dose of 100 mg/kg by intragastric gavage. Four days after the surgery, i.e. 24 h after the last metformin administration, the surviving intestinal obstructed rats (n=8) developed overt intestinal dilation but no biochemical abnormality compared to sham-operated animals (n=7; arterial lactate concentrations respectively 4.87 +/- 0.63 mmol/l and 3.97 +/- 0.30 mmol/l, NS, and serum creatinine concentrations 69.0 +/- 1.7 micromol/l and 68.7 +/- 1.9 micromol/l, NS). By contrast, there was a striking difference with regard to metformin concentrations, decreasing from 2.95 +/- 0.94 mg/l at day 0 to 0.12 +/- 0.03 mg/l at day 4 (p<0.001) in the sham-operated group but remaining unchanged (1.65 +/- 0.76 mg/l and 1.61 +/- 0.51 mg/l) in the operation group. In conclusion, this is the first experiment showing that intestinal occlusion may be responsible for metformin retention in the absence of renal failure. Whether this observation may be relevant to other drugs remains to be established.

Acute Kidney Injury↗

PubMed2001

Therapeutic perspectives for type 2 diabetes mellitus: molecular and clinical insights.

Current antidiabetic agents do not suppress insulin resistance, do not reinstate physiological insulin secretion and fail to prevent the gradual loss of B-cell function. Thus, these molecules are unable to maintain long term euglycemia in all type 2 diabetic patients and there is a need for new antidiabetic drugs. Thiazolidinediones (TZD) are a new class of insulin sensitizers recently approved in Europe, in combination therapy with sulfonylureas or/and metformin, for the treatment of type 2 diabetes. TZD show beneficial effects on insulin action, glucose homeostasis and lipid metabolism despite a substantial weight gain. Their potential protective effect on B-cell function and on the development of macrovascular complication is of particular interest. Non TZD PPARgamma agonists are also under clinical trials. Other interesting therapeutic perspectives to treat insulin resistance lie in the development of inhibitors of protein tyrosine phosphatases and in the promotion of non insulin-dependent contraction-like muscle glucose uptake via stimulation of AMP protein kinase (AMPK). As to new insulin secretagogues, the phenylalanine derivative nateglinide is a first phase insulin secretion enhancer primarily intended at controlling post-prandial hyperglycemia. The most promising perspective to improve B-cell function lies in the development of glucagon-like peptide-1 (GLP-1) analogs. Clinical studies show beneficial effects on glucose homeostasis in type 2 diabetics and efficacy in sulfonylurea resistant patients without risk of hypoglycaemia. Animal studies predict beneficial effects on B-cell mass. Finally we will discuss the potential use of gene therapy to treat insulin resistance and B-cell dysfunction.

Diabetes Mellitus, Type 2↗

PubMed2000

Regulation of gene expression during severe caloric restriction: lack of induction of p85 alpha phosphatidylinositol 3-kinase mRNA in skeletal muscle of patients with type II (non-insulin-dependent) diabetes mellitus.

AIMS/HYPOTHESIS: Alterations in the regulation of gene expression could be involved in the development of Type II (non-insulin-dependent) diabetes mellitus. METHODS: We compared the mRNA concentrations of eight genes encoding proteins involved in insulin action and intermediary metabolism in skeletal muscle of healthy volunteers and Type II diabetic patients. The in vivo regulation of the expression of these genes was investigated after 5 days of hypocaloric diet (1045 kJ/day). RESULTS: In the basal state, diabetic muscle showed reduced insulin receptor (-38%), hexokinase II (-73%), glycogen synthase (-45%) and lipoprotein lipase (-70%) mRNA expression. There was no difference in the mRNA abundances of IRS-1, GLUT 4, p85 alpha phosphatidylinositol-3-kinase (p85 alpha PI3K) or Rad. In both groups, caloric restriction induced weight loss, reduced glycaemia and increased plasma ketone body concentrations. The diet also increased plasma concentrations of fatty acids and decreased whole-body insulin sensitivity in control subjects. In control subjects, the diet increased p85 alpha PI3K (+146%), insulin receptor (+100%) and Rad (+40%) mRNA concentrations in muscle. In Type II diabetic patients, the diet increased insulin receptor (+41%) and Rad (+31%) mRNAs but the expression of p85 alpha PI3K was not modified. CONCLUSION/INTERPRETATION: The regulation of the expression of p85 alpha PI3K is altered during caloric restriction in skeletal muscle of Type II diabetic patients. Because we have shown in an earlier study that there is also a defective regulation of p85 alpha PI3K gene expression in response to insulin, these data support the hypothesis that alterations in the regulation of gene expression could be involved in the pathogenesis of Type II diabetes.

Adult↗

PubMed2000

Subcutaneous adipose tissue expression of tumour necrosis factor-alpha is not associated with whole body insulin resistance in obese nondiabetic or in type-2 diabetic subjects.

BACKGROUND: An association with subcutaneous adipose tissue TNFalpha expression and insulin resistance has been suggested in obesity/type-2 diabetes, but this has not been examined directly. In the first part of the study we investigated whether this association is present in 7 lean, 10 obese nondiabetic and 9 type-2 diabetic men. In the second part of the study we examined the relationship between adipose tissue TNFalpha mRNA levels and BMI in 81 nondiabetic subjects spanning a wide range of BMIs. METHODS: Subcutaneous adipose tissue TNFalpha mRNA levels and insulin sensitivity were determined with quantitative RT-competitive PCR and hyperinsulinaemic clamp, respectively. RESULTS: Subcutaneous adipose tissue TNFalpha mRNA levels were similar in 7 lean and 10 obese nondiabetic and 9 type-2 diabetic men (P = 0.68), and did not change in response to 240-min hyperinsulinaemia. TNFalpha mRNA levels and insulin sensitivity were not correlated. Unexpectedly, no correlation between TNFalpha mRNA and BMI was found. The relationship between adipose tissue TNFalpha mRNA and BMI was examined further in 31 male and 50 female nondiabetic subjects. The subcutaneous adipose tissue TNFalpha mRNA level correlated with BMI in all subjects (rS = 0.32, P < 0.01), and in a subgroup analysis in men (rS = 0.55, P < 0.01) but not in women (rS = - 0.08). The correlation in men was dependent on a fourfold higher TNFalpha mRNA level in 5 morbidly obese men while there was no difference in TNFalpha mRNA levels in lean or obese men. CONCLUSIONS: Subcutaneous adipose tissue TNFalpha expression does not correlate with insulin sensitivity in nondiabetic or type-2 diabetic men; is not regulated by acute hyperinsulinaemia; and is increased only in morbidly obese men.

Adipose Tissue↗

PubMed2000

Fatty acid transport protein-1 mRNA expression in skeletal muscle and in adipose tissue in humans.

Fatty acid transporter protein (FATP)-1 mRNA expression was investigated in skeletal muscle and in subcutaneous abdominal adipose tissue of 17 healthy lean, 13 nondiabetic obese, and 16 obese type 2 diabetic subjects. In muscle, FATP-1 mRNA levels were higher in lean women than in lean men (2.2 +/- 0.1 vs. 0.6 +/- 0.2 amol/microg total RNA, P < 0.01). FATP-1 mRNA expression was decreased in skeletal muscle in obese women both in nondiabetic and in type 2 diabetic patients (P < 0.02 vs. lean women in both groups), and in all women there was a negative correlation with basal FATP-1 mRNA level and body mass index (r = -0.74, P < 0.02). In men, FATP-1 mRNA was expressed at similar levels in the three groups both in skeletal muscle (0.6 +/- 0.2, 0.6 +/- 0.2, and 0.8 +/- 0.2 amol/microg total RNA in lean, obese, and type 2 diabetic male subjects) and in adipose tissue (0.9 +/- 0.2 amol/microg total RNA in the 3 groups). Insulin infusion (3 h) reduced FATP-1 mRNA levels in muscle in lean women but not in lean men. Insulin did not affect FATP-1 mRNA expression in skeletal muscle in obese nondiabetic or in type 2 diabetic subjects nor in subcutaneous adipose tissue in any of the three groups. These data show a gender-related difference in the expression of the fatty acid transporter FATP-1 in skeletal muscle of lean individuals and suggest that changes in FATP-1 expression may not contribute to a large extent to the alterations in fatty acid uptake in obesity and/or type 2 diabetes.

Abdomen↗

PubMed2000

Normal reproductive function in leptin-deficient patients with lipoatropic diabetes.

To further examine the relationships between leptin and female reproductive axis, we conducted hormonal studies in two patients with lipoatropic diabetes that occurred before puberty. Despite complete atrophy of sc and visceral adipose tissue, menarche occurred in these two patients between 11-12 yr of age, followed by regular menstrual cycles. One patient had been pregnant three times, giving birth to children who did not develop the disease. In our two patients, repeated analysis revealed leptin levels below 1 ng/mL (normal range for 20 insulin-treated diabetic women, 2-23 ng/mL for body mass index of 14-39 kg/m2; personal data). We measured peripheral levels of estradiol, progesterone, FSH, LH, free testosterone, and androstenedione within the first 5 days of the menstrual cycle, and we tested the reactivity of pituitary after iv injection of 100 microg GnRH. The variation in body temperature in the morning before arising was also analyzed. We showed that 1) all measured levels of hormones were in the normal range for both patients; and 2) low levels of leptin did not impair the development of reproductive function in one patient and was associated with normal gonadal function in both patients. We conclude that puberty and fertility can occur despite chronic low serum levels of leptin. This suggests that leptin is not fundamental to the maintenance of normal reproductive function in humans.

Adult↗

PubMed2000

Evidence of recurrent type I diabetes following HLA-mismatched pancreas transplantation.

Type 1 diabetes mellitus is considered as an autoimmune disease against beta cells. Diabetes recurrence after pancreas transplantation is well known in HLA-identical twins while it is rarely reported in recipients of cadaveric pancreatic grafts. In the present case report, diabetes recurrence occurred in a recipient who underwent cadaveric combined pancreas kidney transplantation. Seven years after transplantation the patient exhibited progressive hyperglycemia needing insulin therapy while the renal graft was well functioning. The diagnosis of recurrent disease was obtained on the histological features such as selective loss of beta cells without clear signs of insulitis and on the presence of markers (GAD 65 and IA-2) for humoral autoimmunity. It is intriguing that, at the time of recurrence of type 1 diabetes, the patient had stopped steroids and azathioprine, while only cyclosporine was maintained as immunosuppressive treatment. Our case report underlines the relevance of studying the humoral autoimmune response directed to islet autoantigens in cadaveric pancreas allograft recipients. Furthermore, it suggests that an efficient immunosuppressive treatment after transplantation may be able to reduce the autoimmune response against the pancreatic allograft.

Adolescent↗

PubMed2000

[News from UKPDS].

Risk factors present in type 2 diabetic patients at the time of their inclusion in the study were related with the occurrence of some complications. Thus, relative risk for coronary heart disease is 1.57 when HbA1c is > 7.5%, 1.41 when LDL-Cholesterol is > 3.89 mmol/l, these factors are not involved in the occurrence of cerebral stroke. Blood pressure and HbA1c were monitored throughout the study and could have been significantly correlated with the occurrence of micro- and macroangiopathy, with a linear-type and even exponential (HbA1c/retinopathy) relationship and a synergistic interaction between these 2 parameters. A treatment allowing a 0.9% decrease of HbA1c and a 10 mmHg decrease of systolic blood pressure is associated with a reduction of complications, more or less important than that expected from the epidemiological analysis of data. Several therapeutic strategies ensue from these observations.

Cholesterol, LDL↗

PubMed2000

[Mechanisms for weight gain during blood glucose normalization].

Secondary failure to dietary and maximal oral treatment leads to insulin therapy in type 2 diabetic patients. However, weight gain is a frequent side effect of insulin therapy in these patients. Mechanisms for this weight gain are complex. Insulin 1) reduces glycosuria and its caloric expenditure; 2) stimulates the stockage of fatty acids into triglycerides in adipose tissue, thus favoring an increase in adipose mass; 3) yields a positive nitrogen balance through an inhibition of muscle proteolysis, thus favoring an increase in lean mass. Most studies report an average 6 kg weight gain during the first year following the initiation of insulin therapy in type 2 diabetic patients. Analysing body composition variations shows that weight gain results both from an increase in fat mass (mean 63%) and an increase in lean mass (mean 37%). Preexisting obesity does not influence this weight gain. Finally, the 10 year-follow up of UKPDS showed a beneficial effect of insulin therapy on microangiopathy prevention, without increasing cardiovascular mortality as compared with type 2 diabetic patients on oral treatment. Thus, while weight gain seems mandatory, it should not refrain from initiating insulin therapy in poorly controlled type 2 diabetic patients, as its expected beneficial effects on the prevention of microangiopathy seem well established.

Blood Glucose↗

PubMed1999

Defective regulation of phosphatidylinositol-3-kinase gene expression in skeletal muscle and adipose tissue of non-insulin-dependent diabetes mellitus patients.

We investigated the regulation of the mRNA expression of the insulin receptor, insulin receptor substrate-1 (IRS-1) and p85alpha-phosphatidylinositol-3-kinase (PI-3K), three major actors of insulin action, in skeletal muscle from 10 healthy lean volunteers, 13 obese patients with Type II (non-insulin-dependent) diabetes mellitus and 7 non-diabetic obese subjects. The in vivo regulation by insulin was studied using a 3-h euglycaemic, hyperinsulinaemic clamp. There were no differences in the basal concentrations of the three mRNAs in skeletal muscle between groups. Insulin infusion produced a twofold reduction in insulin receptor substrate-1 mRNA expression in the three groups (p<0.02). In contrast, insulin increased p85alpha-phosphatidylinositol-3-kinase mRNA expression in muscle from non-diabetic subjects (+98+/-22% in lean and +127+/-16% in obese, p<0.02) but this effect was totally impaired in Type II diabetic patients (+5+/-12%, NS). A similar defect in insulin action on p85alpha-phosphatidylinositol-3-kinase mRNA expression was observed in abdominal subcutaneous adipose tissue (+138+/-25%, p<0.01 in lean and +46+/-14%, p<0.02 in obese and +29+/-11%, NS in Type II diabetic patients). The lack of action of insulin on p85alpha-phosphatidylinositol-3-kinase mRNA in diabetic subjects was probably not due to a deleterious effect of hyperglycaemia since improvement of the glycaemic control for 10 days did not restore the response in muscle or in adipose tissue. This study provides evidence for a defect in the regulation by insulin of PI-3K gene expression in Type II diabetic patients, thus reinforcing the concept that alterations at the gene expression might be involved in the pathogeny of Type II diabetes.

Adipose Tissue↗

PubMed1999

Uncoupling protein-2 (UCP2) and uncoupling protein-3 (UCP3) expression in adipose tissue and skeletal muscle in humans.

Uncoupling protein-2 (UCP2) and uncoupling protein-3 (UCP3) are mitochondrial proteins that may play a role in the control of energy expenditure by uncoupling respiration from ATP synthesis. The present review focuses on data obtained in humans. UCP2 is widely expressed in the body, whereas UCP3 expression is restricted to skeletal muscle. Positive correlations have been reported between UCP2 mRNA concentrations in adipose tissue, UCP3 mRNA concentrations in skeletal muscle, and components of the metabolic rate. Fasting induces an up-regulation of UCP2 and UCP3 mRNA expression. In vivo and in vitro studies suggest that fatty acids could modulate uncoupling protein gene expression. The putative relationship between obesity, energy expenditure and uncoupling protein expression, and the unexpected rise in UCP2 and UCP3 mRNA concentrations during short-term fasting, are discussed in view of the recent data obtained in rodents and cell lines.

Adipose Tissue↗

PubMed1999

Cloning and mRNA tissue distribution of human PPARgamma coactivator-1.

OBJECTIVES: To determine human PPARgamma coactivator-1 (PGC-1) amino acid sequence and to study PGC-1 mRNA tissue distribution. PGC-1 is a novel transcriptional coactivator of nuclear receptors that may play a role in the control of thermogenesis. SUBJECTS: Subcutaneous adipose tissue was obtained from six obese and five lean male subjects. Vastus lateralis skeletal muscle was obtained from seven lean and six obese subjects undergoing a 5-day severe calorie restriction. Other tissue biopsies were from nonobese nondiabetic subjects. METHODS: Human PGC-1 was cloned from a skeletal muscle cDNA library. A reverse transcription-competitive polymerase chain reaction assay was developed to determine PGC-1 mRNA levels in human tissues. RESULTS: The human amino acid sequence showed 95% identity with mouse PGC-1. PGC-1 mRNA was expressed at very low levels in the small and large intestines and white adipose tissue. Heart, kidney, liver and skeletal muscle showed higher mRNA levels. The degree of obesity did not affect PGC-1 mRNA levels in adipose tissue while lean subjects expressed more PGC-1 mRNA than obese subjects in skeletal muscle. A 5-day severe calorie restriction induced PGC-1 mRNA expression in skeletal muscle of obese but not of lean subjects. CONCLUSION: PGC-1 shows a restricted tissue expression that suggests a tissue-specific role in the control of gene transcription and possible interaction with various members of the PPAR family. The lower expression of skeletal muscle PGC-1 in obesity could contribute to an alteration of mitochondrial gene expression.

Adipose Tissue↗