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Biomedical subjects

K Clément

Publications and source records attributed to K Clément.

At least 19 recordsLinked to original sources
PubMed2006

Is obesity an inflammatory illness? Role of low-grade inflammation and macrophage infiltration in human white adipose tissue.

There are at least two scientific evidences of human obesity as a chronic inflammatory illness: first, the well-described moderate increase of inflammatory factors in the circulation in obese subjects, and second, the recent identification of macrophage cells infiltrating the white adipose tissue (WAT). These observations led to a revision of the physiopathology of obesity and its co-morbidities. It has been suggested that the 'low-grade' inflammatory state associates with metabolic and cardiovascular complications of obesity. Weight loss is able to improve this inflammatory state by both significantly decreasing circulating inflammatory molecules and macrophage cell infiltration in WAT depots. However, the mechanisms of WAT macrophage recruitment into the adipose tissue and their role in obesity complications have not been defined. This review aims to point out the knowledge on inflammatory cytokines associated with obesity and focuses on macrophage infiltration in human WAT, discussing their recruitment and role. The interactions of macrophages with adipocytes will certainly be the subject of intense investigations in the future.

Adipocytes↗
PubMed2006

Microarray profiling of human white adipose tissue after exogenous leptin injection.

BACKGROUND: Leptin is a secreted adipocyte hormone that plays a key role in the regulation of body weight homeostasis. The leptin effect on human white adipose tissue (WAT) is still debated. OBJECTIVE: The aim of this study was to assess whether the administration of polyethylene glycol-leptin (PEG-OB) in a single supraphysiological dose has transcriptional effects on genes of WAT and to identify its target genes and functional pathways in WAT. MATERIALS AND METHODS: Blood samples and WAT biopsies were obtained from 10 healthy nonobese men before treatment and 72 h after the PEG-OB injection, leading to an approximate 809-fold increase in circulating leptin. The WAT gene expression profile before and after the PEG-OB injection was compared using pangenomic microarrays. Functional gene annotations based on the gene ontology of the PEG-OB regulated genes were performed using both an 'in house' automated procedure and GenMAPP (Gene Microarray Pathway Profiler), designed for viewing and analyzing gene expression data in the context of biological pathways. RESULTS: Statistical analysis of microarray data revealed that PEG-OB had a major down-regulated effect on WAT gene expression, as we obtained 1,822 and 100 down- and up-regulated genes, respectively. Microarray data were validated using reverse transcription quantitative PCR. Functional gene annotations of PEG-OB regulated genes revealed that the functional class related to immunity and inflammation was among the most mobilized PEG-OB pathway in WAT. These genes are mainly expressed in the cell of the stroma vascular fraction in comparison with adipocytes. CONCLUSION: Our observations support the hypothesis that leptin could act on WAT, particularly on genes related to inflammation and immunity, which may suggest a novel leptin target pathway in human WAT.

Adipocytes↗
PubMed2006

Increased adiponectin receptor-1 expression in adipose tissue of impaired glucose-tolerant obese subjects during weight loss.

OBJECTIVE: To investigate the mRNA expression of adiponectin, AdipoR1 and AdipoR2, the two recently cloned adiponectin receptors and peroxisome proliferator activated receptor (PPAR)gamma2 in adipose tissue of obese individuals before and during a very low calorie diet (VLCD) inducing weight loss. METHODS: Twenty-three non-diabetic obese subjects with normal (NGT, n = 11) or impaired glucose tolerance (IGT, n = 12) (age, 47 +/- 3 years; body mass index, 39.3 +/- 1.3 kg/m2) were studied before and after a 3-week 3.9 MJ diet daily without exercise. mRNA levels of nine IGT and six NGT subjects were measured by real-time PCR in s.c. abdominal adipose tissue. RESULTS: Metabolic parameters and insulin sensitivity were improved by VLCD in the IGT group, but minimally affected in the NGT group. VLCD increased expression of AdipoR1 in the IGT (P = 0.02), but not in the NGT group. Adiponectin, AdipoR2 and PPARgamma2 mRNA levels did not change during VLCD in any group. In the IGT, but not in the NGT group, AdipoR1 and AdipoR2 expressions were positively related to that of PPARgamma2 and, after VLCD, AdipoR1 and AdipoR2 expressions were positively related to each other and to that of adiponectin. CONCLUSION: In the NGT group, the 3-week VLCD inducing weight loss did not modify metabolic parameters, insulin sensitivity and the expression of the adiponectin system in adipose tissue. By contrast, in the IGT group, AdipoR1 expression increased and we found a coordinate regulation of the expression of adiponectin and its receptors. These modifications could participate, through adiponectin action on adipocytes, to the improved metabolic parameters observed in IGT subjects.

Adipose Tissue↗
PubMed2005

Hypoadiponectinaemia and high risk of type 2 diabetes are associated with adiponectin-encoding (ACDC) gene promoter variants in morbid obesity: evidence for a role of ACDC in diabesity.

AIMS/HYPOTHESIS: Morbid obesity (BMI>40 kg/m(2)) affecting 0.5-5% of the adult population worldwide is a major risk factor for type 2 diabetes. We aimed to elucidate the genetic bases of diabetes associated with obesity (diabesity), and to analyse the impact of corpulence on the effects of diabetes susceptibility genes. METHODS: We genotyped known single nucleotide polymorphisms (SNPs) in the adiponectin-encoding adipocyte C1q and collagen-domain-containing (ACDC) gene (-11,391G>A, -11,377C>G, +45T>G and +276G>T), the peroxisome proliferator-activated receptor gamma (PPARG) Pro12Ala SNP and ACDC exon 3 variants in 703 French morbidly obese subjects (BMI 47.6+/-7.4 kg/m(2)), 808 non-obese subjects (BMI<30 kg/m(2)) and 493 obese subjects (30< or =BMI<40 kg/m(2)). RESULTS: Two 5'-ACDC SNPs -11,391G>A, -11,377C>G were associated with adiponectin levels (p=0.0003, p=0.008) and defined a "low-level" haplotype associated with decreased adiponectin levels (p=0.0002) and insulin sensitivity (p=0.01) and with a risk of type 2 diabetes that was twice as high (p=0.002). In contrast, the prevalence of the PPARG Pro12Ala was identical in diabetic and normoglycaemic morbidly obese subjects. The PPARG Pro12 allele only displayed a trend of association with type 2 diabetes in the non-obese group. ACDC exon 3 variants were associated with type 2 diabetes in the non-obese group only (odds ratio 7.85, p<0.0001). In contrast, the 5'-ACDC "low-level" haplotype was associated with type 2 diabetes in obese and morbidly obese subjects (odds ratio 1.73 and 1.92) but not in non-obese individuals. CONCLUSIONS/INTERPRETATION: These data clarify the contribution of the 5'-ACDC SNPs to the risk of diabesity. Their interaction with corpulence suggests for the first time a different genetic profile of type 2 diabetes in morbidly obese patients compared with in less obese individuals.

Adiponectin↗
PubMed2005

Serum amyloid A: production by human white adipocyte and regulation by obesity and nutrition.

AIMS/HYPOTHESIS: The acute-phase proteins, serum amyloid As (SAA), are precursors of amyloid A, involved in the pathogenesis of AA amyloidosis. This work started with the characterisation of systemic AA amyloidosis concurrent with SAA overexpression in the subcutaneous white adipose tissue (sWAT) of an obese patient with a leptin receptor deficiency. In the present study a series of histopathological, cellular and gene expression studies was performed to assess the importance of SAA in common obesity and its possible production by mature adipocytes. MATERIALS AND METHODS: Gene expression profiling was performed in the sWAT of two extremely obese patients with a leptin receptor deficiency. Levels of the mRNAs of the different SAA isoforms were quantified in sWAT cellular fractions from lean subjects and from obese subjects before and after a very-low-calorie diet. These values were subsequently compared with serum levels of SAA in these individuals. In addition, histopathological analyses of sWAT were performed in lean and obese subjects. RESULTS: In sWAT, the expression of SAA is more than 20-fold higher in mature adipocytes than in the cells of the stroma vascular fraction (p<0.01). Levels of SAA mRNA expression and circulating levels of the protein are sixfold (p<0.001) and 3.5-fold (p<0.01) higher in obese subjects than in lean subjects, respectively. In lean subjects, 5% of adipocytes are immunoreactive for SAA, whereas the corresponding value is greater than 20% in obese subjects. Caloric restriction results in decreases of 45-75% in levels of the transcripts for the SAA isoforms and in circulating levels of the protein. CONCLUSIONS/INTERPRETATION: The results of the present study indicate that SAA is expressed by sWAT, and its production at this site is regulated by nutritional status. If amyloidosis is seen in the context of obesity, it is possible that production of SAA by adipocytes could be a contributory factor.

Adipocytes↗
PubMed2005

Transcriptomics applied to obesity and caloric restriction.

Caloric restriction still remains the most efficient way to promote weight loss. Deciphering the molecular basis of adaptation to energy restriction is critical for the tailoring of new therapeutic strategies. This review focuses on the recent input of gene profiling on adipose tissue in obesity pathogenesis and on the new insights on adaptations occurring during very low caloric diet (VLCD) in humans. Hypocaloric diets improve a wide range of metabolic parameters including lipolytic efficiency, insulin sensitivity, and inflammatory profile. In the subcutaneous white adipose tissue (scWAT) the VLCD induced a decrease in the mRNA levels for the antilipolytic alpha2-adrenergic receptor associated with changes in catecholamine-induced adipocyte lipolytic capacity. The improvement in insulin sensitivity was not associated with a change in subcutaneous adipose tissue adiponectin gene expression or in its plasma level, suggesting that adiponectin is not involved in the regulation of VLCD-induced improvement of insulin sensitivity and that there is a small contribution of subcutaneous adipose tissue to plasma adiponectin levels. Pangenomic microarray studies in human scWAT revealed that a panel of inflammatory markers and acute phase reactants were over expressed in obese compared to lean subjects. Caloric restriction improved the inflammatory profile of obese subjects through a decrease of pro-inflammatory factors and an increase of anti-inflammatory molecules. These genes were mostly expressed in the stroma vascular fraction of the adipose tissue. Specific cell-type isolation and immunohistochemistry demonstrated that monocyte/macrophage lineage cells were responsible for the expression of both mRNA and protein inflammatory markers. The acute phase proteins serum amyloid A was highly expressed in mature adipocytes from obese subjects. Caloric restriction decreased both serum amyloid mRNA and circulating levels. Obesity now clearly appears as chronic low-grade inflammation state. Modulation of the inflammatory pathways may represent new therapeutic targets for the treatment of obesity-related complications.

Adipose Tissue↗
PubMed2005

[Genetics of human obesity].

BACKGROUND: Both genetic and environmental aspects are recognized in the obesity field but we are not able to elucidate multiple genes and gene-environment interactions with the present resources and tools used in the study of this complex disease. The purpose of this paper is to present some examples of the knowledge acquired in the field of obesity genetics and the new ongoing tools and developments that aim at studying the contribution of genes to obesity and their response to environmental changes. MAIN POINTS: In rare cases of monogenic obesities, genetic tools have proved extremely powerful for identifying the genes responsible and for defining new syndromes. However, in common obesity, most studies include the search for genotype-phenotype associations without taking into account the influence of environment (diet, sedentary lifestyle) in the relationship. Among the limitations to this integrated approach, one can cite the difficulty of having large enough samples as well as biocomputing tools that are still in their infancy for accessing the question of multiple interactions with no "a priori hypotheses". This picture will probably change rapidly in the future. PERSPECTIVE: Large databases and DNA and biological sample banks will be available with updated environmental information and precise phenotypes thanks especially to European working groups. The capacity for studying multiple genes at once at the DNA or RNA levels is rapidly growing. Finally, tremendous progress in biocomputing will allow the integration of information from different sources (i.e. environment, phenotype, genotype, gene expression) and thus improve our ability to deal with complexity.

Adult↗
PubMed2004

Adipose tissue gene expression in obese subjects during low-fat and high-fat hypocaloric diets.

AIMS/HYPOTHESIS: Adaptation to energy restriction is associated with changes in gene expression in adipose tissue. However, it is unknown to what extent these changes are dependent on the energy restriction as such or on the macronutrient composition of the diet. METHODS: We determined the levels of transcripts for 38 genes that are expressed in adipose tissue and encode transcription factors, enzymes, transporters and receptors known to play critical roles in the regulation of adipogenesis, mitochondrial respiration, and lipid and carbohydrate metabolism. Two groups of 25 obese subjects following 10-week hypocaloric diet programmes with either 20-25 or 40-45% of total energy derived from fat were investigated. Levels of mRNA were measured by performing real-time RT-PCR on subcutaneous fat samples obtained from the subjects before and after the diets. RESULTS: The two groups of subjects lost 7 kg over the duration of the diets. Ten genes were regulated by energy restriction; however, none of the genes showed a significantly different response to the diets. Levels of peroxisome proliferator-activated receptor gamma co-activator 1alpha mRNA were increased, while the expression of the genes encoding leptin, osteonectin, phosphodiesterase 3B, hormone-sensitive lipase, receptor A for natriuretic peptide, fatty acid translocase, lipoprotein lipase, uncoupling protein 2 and peroxisome proliferator-activated receptor gamma was decreased. Clustering analysis revealed new potential coregulation of genes. For example, the expression of the genes encoding the adiponectin receptors may be regulated by liver X receptor alpha. CONCLUSIONS/INTERPRETATION: In accordance with the comparable loss of fat mass produced by the two diets, this study shows that energy restriction and/or weight loss rather than the ratio of fat: carbohydrate in a low-energy diet is of importance in modifying the expression of genes in the human adipose tissue.

Adipose Tissue↗
PubMed2004

Single nucleotide polymorphisms of protein tyrosine phosphatase 1B gene are associated with obesity in morbidly obese French subjects.

AIMS/HYPOTHESIS: The development of insulin resistance may contribute to the occurrence and progression of the metabolic syndrome associated with obesity. Components contributing to the insulin pathway and its regulation are good candidates for the molecular study of metabolic syndrome pathogenesis. Protein tyrosine phosphatase 1B (PTP 1B) is an important negative regulator of insulin. We investigated whether PTP 1B SNPs are associated with obesity and obesity-related traits as well as global metabolic syndrome in morbidly obese subjects. METHODS: Untranslated and coding regions of the PTP 1B gene were screened in groups of non-diabetic and diabetic obese subjects and in non-obese subjects. Unrelated morbidly obese ( n=711) and non-obese ( n=427) French Caucasian subjects were genotyped for a case-control study. RESULTS: Six SNPs were identified: two rare variants were located in 5'UTR (-109 C>T and -69 C>T), two in the intronic regions (IVS3+38 G>T and IVS5+3666delT) and two have been described previously (P303P in exon 8 and P387L in exon 9). A case-control study showed an association between the frequent IVS5+3666delT SNP and obesity ( p=0.02). In the obese group, associations between PTP 1B SNPs and features of dyslipidaemia were found. P303P was associated with lower apolipoprotein A1 levels ( p=0.05) whereas P387L was associated with higher triglyceride ( p=0.0003), apolipoprotein B ( p=0.09) and lipoprotein a concentrations ( p=0.006). CONCLUSIONS/INTERPRETATION: Our results support the hypothesis that the PTP 1B gene contributes to the polygenic basis of obesity. PTP 1B SNPs may interact with environmental factors to induce more severe phenotypes, e.g. atherogenic dyslipidaemia, in morbidly obese subjects.

Cholesterol↗
PubMed2004

Adiposity signals, genetic and body weight regulation in humans.

Numerous signals convey information about body fat status from the periphery to the brain areas that control energy homeostasis so that, throughout life, body weight remains nearly stable. These signals mainly originate, either from the adipose tissue, like leptin and to a lesser extent interleukin 6, or from the pancreas, like insulin and amylin. These factors circulate in proportion to body fat mass and they are referred to as "adiposity signals". It is well established, at least for leptin and insulin, that they enter the brain from the plasma where they induce/repress a network of important neuropeptide regulators of energy intake and expenditure. Beside these endocrine signals, a growing amount of literature show data relative to adipocyte-derived molecules, most of them belonging to the cytokine family, like IL6, TNFalpha, IL8, IL10 whose secretion also correlates with body fat mass and that may locally regulate fat mass expansion. Others, like adiponectin, are negatively correlated with body fat mass. These "adiposity molecules" have already been involved in insulin resistance associated with obesity and inflammatory process. They may participate to a complex inter organ dialogue. In this review, we will synthesize data relative to the role played by insulin, leptin and amylin, either alone or through a cross talk, in "energy level sensing" at the brain level. Furthermore, we will develop how "adiposity molecules" through their paracrin and/or autocrin action may contribute to maintain fat mass expansion, therefore representing new adiposity molecules per se. Lastly, since any distortion in the metabolic circuitry of energy homeostasis is susceptible to lead to a pathological status like obesity, the impact of known genetic polymorphisms in genes encoding the adiposity signals will be discussed.

Adipose Tissue↗
PubMed2002

Adipose tissue gene expression in patients with a loss of function mutation in the leptin receptor.

BACKGROUND: In order to maintain body weight regulation, leptin directly or indirectly signals nutritional changes to key organs, but little is known about its target genes in human adipose tissue. Leptin receptor loss of function is a unique way to explore the role of leptin in the regulation of adipose tissue. OBJECTIVE: We studied the consequences of the absence of leptin signaling on adipocyte gene expression in two girls with a mutation in the leptin receptor. The expression levels of the ob gene and adipocyte transcription factors (SREBP1c, C/EPBalpha, beta, PPARgamma1, gamma2) were quantified by RT-PCR in subcutaneous adipose tissue of these patients and of 10 morbidly obese women. RESULTS: Ob mRNA levels in subjects lacking the leptin receptor were not overexpressed but were in the range that could be expected from their BMI (58 and 26 amol/ micro g total mRNA, range in obese women: 26-69). Expression of the five transcription factors was also in the same range in the affected patients and in morbidly obese women (7.7 and 6.8 amol/ micro g total mRNA, range: 2.2-9.4 for SREBP1c, 159 and 51 range: 51-406 for C/EPBalpha, 6.1 and 3.3 range: 2.4-24.8 for C/EPBbeta, 16.7 and 27.4 range: 9.4-29.7 for PPARgamma1 and 1.7 and 5.4 amol/ micro g total mRNA range: 1.7-8.8 for PPARgamma2). Significant correlation was found between the mRNA levels of leptin and PPARgamma2 and leptin and C/EBPalpha whereas no correlation was observed between leptin and SREBP1c, PPARgamma1, or C/EBPbeta mRNA levels. CONCLUSION: In patients lacking leptin signaling, the fact that ob gene expression is adequately adapted to their body fat mass argues against a direct negative feedback loop in the regulation of leptin expression in humans. The normal expression of several transcription factors, known to be dependent of the nutritional status, suggests that leptin is not a major contributor of their in vivo transcriptional regulation in human adipose tissue.

Adipocytes↗
PubMed2001

Mutational analysis of melanocortin-4 receptor, agouti-related protein, and alpha-melanocyte-stimulating hormone genes in severely obese children.

OBJECTIVE: To search for mutations in melanocortin pathway elements, that is, the melanocortin-4 receptor (MC4R ), agouti-related protein (AGRP ), and (alpha-melanocyte-stimulating hormone (alpha MSH ) genes in children with severe obesity. STUDY DESIGN: Direct sequencing of the MC4R encoding sequence and single-strand polymorphism conformation analysis of AGRP and alpha MSH genes were performed in 63 severely obese children. Polymerase chain reaction (PCR) assays of restriction fragment length polymorphism were used to assess the frequency of each newly discovered mutation in 283 non-obese control subjects. RESULTS: Four dominantly inherited, heterozygous, missense MC4R mutations (Val50Met, Ser58Cys, Ile102Ser, and Ile170Val) were identified in 4 unrelated children and none of the control subjects. Expression of the obese phenotype was variable in mutation-positive family members. Clinical and laboratory features were similar in the obese children with and without an MC4R mutation. Two polymorphisms were detected in the AGRP -encoding sequence (a silent mutation in exon 1 and Ala67Thr in exon 2), with similar frequencies in the obese and control groups. No mutations were found in the alpha MSH gene. CONCLUSIONS: MC4R mutations may be a non-negligible cause of severe obesity in children with variable expression and penetrance. Mutations in AGRP and alpha MSH genes were not among the causes of obesity in our population.

Adolescent↗
PubMed2000

Genetics of obesity: towards the understanding of a complex syndrome.

GENETICS AND ENVIRONMENT: Obesity is a multifactorial disease combining the effects of genetic predisposition with very powerful environmental risk factors. Recent genetic studies have demonstrated that there is a continuum between different forms of human obesity. SINGLE GENE FACTORS: In certain cases, mainly cases of very severe obesity with childhood onset, a single gene would play a permissive role allowing environmental factors to have major impact. Rare mutations of the leptin gene and its receptor, proopiomelanocortin, or more frequently, melanocortin receptor 4 mutations, are evidence of the existence of an obesity gene. Inactivity of this gene would be sufficient to produce early onset anomalous eating habits. COMMON OBESITY: The more common forms of obesity are however polygenic. The strong environmental pressure exceeds the capacity for homeostatic adaptation of genetically predisposed persons, leading to an energy imbalance favoring fat storage. WHICH GENES? Certain candidate genes, such as decoupling genes, beta-3 adrenergic receptor genes, or regulator regions of the leptin gene, play a minor role in the constitution or aggravation of overweight. Recently, "whole genome" explorations in obese families have localized major obesity genes on chromosomes 2, 5, 10, 11, and 20. Identification of these genes with positional cloning and functional genomic techniques will be helpful in better understanding the molecular determinants of obesity and better defining targets for new therapies.

Animals↗
PubMed2000

Linkage and association studies between the proopiomelanocortin (POMC) gene and obesity in caucasian families.

AIMS/HYPOTHESIS: The region 2p21-23, containing the proopiomelanocortin gene (POMC), was reported to be linked to leptin concentrations in Mexican-American, French and African-American cohorts. A polyhormone peptide, POMC is expressed in brain, gut, placenta and pancreas. The POMC mutations are responsible for rare cases of early-onset obesity. Thus we examined the contribution of the POMC locus to obesity in French families. METHODS: Single and multipoint linkage studies were done between obesity, obesity associated-phenotypes (leptin values and z-score of the body mass index) and three newly mapped markers surrounding POMC in 264 affected sib-pairs from French obese families. Mutation screening of the exons and intron/exon junctions of the POMC gene was realised by direct sequencing. Association studies were done in 379 unrelated obese patients and 370 non-obese non-diabetic subjects. RESULTS: Linkage analysis confirmed the trend towards linkage between polymorphic markers around POMC and variations of leptin concentrations and z-score (maximum lod score at D2S2337 = 2.03). Mutation screening of the POMC gene in the French Caucasian cohort identified two previously reported polymorphisms. None of these variants was associated with obesity, diabetes or serum leptin and lipid concentrations. CONCLUSION/INTERPRETATION: Our results indicate that mutations in the POMC gene do not contribute to the variance of obesity associated phenotypes, at least in French Caucasians. Given the replicated evidence of linkage between leptin values and the chromosome 2p21-23 region in different populations, it is likely that functional variant(s) in the POMC regulating sequences or in an unknown gene in this region explains this linkage.

Body Mass Index↗
PubMed2000

[Monogenic forms of obesity: from mice to human].

The cloning of five rodent obesity genes has constituted a major advance in our understanding of body weight homeostasis. Breakthroughs in human molecular genetics have identified mutations disrupting either rodent homologue/analogue genes or genes involved in the same pathways in obese patients. Three rare cases of human morbid obesity of early onset associated with hypogodatropic hypogodanism are due to mutations in the leptin and the leptin receptor genes. These studies have confirmed that leptin plays not only a crucial role in the control of body weight in the human but also in several endocrine functions. Other Human obesity syndromes are linked to mutations in the genes encoding brain-expressed targets of leptin, particularly some key components of the melanocortin system. Patients compound heterozygous for mutations in the POMC gene display severe obesity of early onset, congenital adrenal insufficiency and red hair. Another genetic cause of obesity is due to mutation in the Proconvertase gene (PC1), the enzyme required for the cleavage of POMC into ACTH and alpha MSH, and also of Proinsulin to insulin. The subject compound heterozygous for the PC1 mutation displays besides obesity, a partial ACTH deficiency, elevated POMC and late post absorptive hypoglycemia due to the accumulation of high pro-insulinemia. Contrasting largely with these rare syndromic forms of obesity, several mutations located in the melanocortin 4 receptor gene have been showed to cause an early onset dominant form of obesity with no other associated abnormalities indifferent populations. These mutations in MC4-R could represent a "frequent" cause of common monogenic forms of obesity in human. More generally, these researches into human obesity have opened new exciting understandings in some of the pathways regulating body fat mass.

Adrenocorticotropic Hormone↗
PubMed1999

Leptin and the genetics of obesity.

The discovery of the Ob gene and its product, leptin, is a good example of the contribution made by molecular biology to the understanding of mechanisms initially hypothesized from classic physiological studies. Leptin is produced in adipose tissue and acts on the central nervous system to regulate multiple neuroendocrine secretions. In three rare cases of human morbid obesity, the discovery of mutations in the leptin and leptin receptor genes shows that leptin plays a crucial role in the control of weight and several endocrine functions (particularly reproduction). These studies also illustrate the limits of genetics in the investigation of monogenic forms of animal obesity, and the difficulties of linking molecular findings to the pathophysiology of complex diseases, such as human common obesity. Previous searches for mutations in the leptin and leptin receptor genes indicated that these are probably not major genes for common forms of human obesity. This review focuses on the recent molecular findings that have indicated a putative role for the leptin axis in human obesity.

Animals↗
PubMed1999

Insulin secretion and insulin sensitivity in diabetic and non-diabetic subjects with hepatic nuclear factor-1alpha (maturity-onset diabetes of the young-3) mutations.

OBJECTIVE: To evaluate insulin secretion and sensitivity in affected (diabetes mellitus or impaired glucose tolerance; n=7) and in unaffected (normal glucose tolerance; n=3) carriers of hepatocyte nuclear factor-1alpha (maturity-onset diabetes of the young-3 (MODY3)) gene mutations. METHODS: Insulin secretion was assessed by an i.v. glucose tolerance test (IVGTT), hyperglycemic clamp and arginine test, and insulin sensitivity by an euglycemic hyperinsulinemic clamp. Results were compared with those of diabetic MODY2 (glucokinase-deficient) and control subjects. RESULTS: The amount of insulin secreted during an IVGTT was decreased in affected MODY3 subjects (46+/-24 (s.d.) pmol/kg body weight (BW)) as compared with values in MODY2 (120+/-49pmol/kg BW) and control (173+/-37pmol/kg BW; P=0.0004) subjects. The amount of insulin secreted during a 10mmol/l glucose clamp was decreased in affected MODY3 subjects (171+/-78pmol/kg BW) and MODY2 subjects (302+/-104pmol/kg BW) as compared with control subjects (770+/-199pmol/kg BW; P=0.0001). Insulin secretion in response to arginine was decreased in affected MODY3 subjects. Milder and heterogeneous defects were observed in the unaffected MODY3 subjects; the amount of insulin secreted during the hyperglycemic clamp was 40-79% of that of controls. The response to arginine was abnormally delayed. Insulin sensitivity was decreased in diabetic but not in non-diabetic MODY3 subjects. CONCLUSIONS: Beta-cell dysfunction in response to glucose and arginine is observed in affected and unaffected MODY3 subjects. The MODY3 and MODY2 subtypes present different insulin secretion profiles. Secondary insulin resistance might contribute to the chronic hyperglycemia of MODY3 patients and modulate their glucose tolerance.

Adolescent↗