Leptin, the gene product of the obese gene, may play an important role in regulating body weight by signalling the size of the adipose tissue mass. Plasma leptin was found to be highly correlated with body mass index (BMI) in rodents and in 87 lean and obese humans. In humans, there was variability in plasma leptin at each BMI suggesting that there are differences in its secretion rate from fat. Weight loss due to food restriction was associated with a decrease in plasma leptin in samples from mice and obese humans.

Leptin levels in human and rodent : Measurement of plasma leptin and ob RNA in obese and weight-reduced subjects

An Antidiabetic Thiazolidinedione Is a High Affinity Ligand for Peroxisome Proliferator-activated Receptor γ (PPARγ)

Stimulation of adipogenesis in fibroblasts by PPAR gamma 2, a lipid-activated transcription factor.

I. Introduction II. Molecular Aspects A. PPAR isotypes: identity, genomic organization and chromosomal localization B. DNA binding properties C. PPAR ligand-binding properties D. Alternative pathways for PPAR activation E. PPAR-mediated transactivation properties III. Physiological Aspects A. Differential expression of PPAR mRNAs B. PPAR target genes and functions in fatty acid metabolism C. PPARs and control of inflammatory responses D. PPARs and atherosclerosis E. PPARs and the development of the fetal epidermal permeability barrier F. PPARs, carcinogenesis, and control of the cell cycle IV. Conclusions

Peroxisome proliferator-activated receptors: nuclear control of metabolism.

AdipoQ is a novel adipose-specific gene dysregulated in obesity.

Obesity is associated with an increased incidence of infection, diabetes, and cardiovascular disease, which together account for most obesity-related morbidity and mortality. Decreased expression of leptin or of functional leptin receptors results in hyperphagia, decreased energy expenditure, and obesity. It is unclear, however, whether defective leptin-dependent signal transduction directly promotes any of the conditions that frequently complicate obesity. Abnormalities in tumor necrosis factor α expression have been noted in each of the above comorbid conditions, so leptin deficiency could promote these complications if leptin had immunoregulatory activity. Studies of rodents with genetic abnormalities in leptin or leptin receptors revealed obesity-related deficits in macrophage phagocytosis and the expression of proinflammatory cytokines both in vivo and in vitro. Exogenous leptin up-regulated both phagocytosis and the production of proinflammatory cytokines. These results identify an important and nov...

https://faseb.onlinelibrary.wiley.com/doi/pdf/10.1096/fsb2fasebj.12.1.57

Leptin regulates proinflammatory immune responses

INTRODUCTION . . . • . . . . . . • . . . . . . . . . . . . . . . . . . . . . . . . . • • . . . . . . . . • . • . . . . . . • 99 CELL CULTURE MODELS FOR ADIPOCYTE DEVELOPMENT . • • . . . . . . • . • . . . . 101 Multipotent Stem-Cell Lines . • • • . • . • • • • • . • . • . • • • • • • . • • • • • • • • • . • . • • • • • . • • . 101 Preadipocyte Cell Lines . . . . . . . . • . . . . . . . . • . . . . . • • . • . . . • • • • • . . . . . • . • . . . . . . 102 EXTERNAL MODULATORS OF PREADIPOCYTE DIFFERENTIATION . . • • . • • . • 105 TIlE DEVELOPMENT PROGRAM . . . . • . . . . . . . • . . . . . . . . . . . . . . . . • • . . . . . . . • . . 106 Determination . • . • . • • • . • • . • . • . • • . . • . • . • • • . • . • • • • • • • • • • • . • • • • • • . • • • • . . • • 106 CelVCell Contact at Confluence . . . . • . . . . . . . . . . . . . . . • . . . . . . . . . • . . . . . . • . . • . 107 Induction 0/ Diff erentiation . . . . . . . . . . . . . . . . . . . . . . . . . • . . . . . . • . . . . . . . . • . . . . 107 Terminal Diff erentiation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . • . 108 TRANSCRIPTIONAL CONTROL OF ADIPOCYTE GENES DURING DIFFERENTIATION . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 109 Trans-Acting Factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . • . . . . • • . . . . . . . . • . • . . . . . 109 Expression o/Transcription Factors During Development . . . . . . . . . . . . . . . . . . . . ll8

Regulation of Adipocyte Development

Previous studies have shown that differentiation of 3T3-L1 preadipocytes leads to the transcriptional activation of a group of adipose-specific genes. As an approach to defining the mechanism responsible for activating the expression of these genes, we investigated the binding of nuclear factors to the promoters of two differentiation-induced genes, the 422(aP2) and stearoyl-CoA desaturase 1 (SCD1) genes. DNase I footprinting and gel retardation analysis identified two binding regions within the promoters of each gene that interact with nuclear factors present in differentiated 3T3-L1 adipocytes. One differentiation-induced nuclear factor interacts specifically with a single binding site in the promoter of each gene. Competition experiments showed that the interaction of this nuclear factor with the SCD1 promoter was prevented specifically by a synthetic oligonucleotide corresponding to the site footprinted in the 422(aP2) promoter. Several lines of evidence indicate that the differentiation-induced nuclear factor is CCAAT/enhancer binding protein (C/EBP), a DNA-binding protein first isolated from rat liver. Bacterially expressed recombinant C/EBP binds to the same site at which the differentiation-specific nuclear factor interacts within the promoter of each gene. Northern analysis with RNA from 3T3-L1 cells shows that C/EBP mRNA abundance increases markedly during differentiation. Transient cotransfection studies using a C/EBP expression vector demonstrate that C/EBP can function as a trans-activator of both the 422(aP2) and SCD1 gene promoters.

/pdf/differentiation-induced-gene-expression-in-3t3-l1-2j45mz0u9q.pdf

Differentiation-induced gene expression in 3T3-L1 preadipocytes: CCAAT/enhancer binding protein interacts with and activates the promoters of two adipocyte-specific genes.

A mutation within the obese gene was recently identified as the genetic basis for obesity in the ob/ob mouse. The obese gene product, leptin, is a 16-kDa protein expressed predominantly in adipose tissue. Consistent with leptin's postulated role as an extracellular signaling protein, human embryonic kidney 293 cells transfected with the obese gene secreted leptin with minimal intracellular accumulation. Upon differentiation of 3T3-L1 preadipocytes into adipocytes, the leptin mRNA was expressed concomitant with mRNAs encoding adipocyte marker proteins. A factor(s) present in calf serum markedly activated expression of leptin by fully differentiated 3T3-L1 adipocytes. A 16-hr fast decreased (by approximately 85%) the leptin mRNA level of adipose tissue of lean (ob/+ or +/+) mice but had no effect on the approximately 4-fold higher level in obese (ob/ob) littermates. Since the mutation at the ob locus fails to produce the functional protein, yet its cognate mRNA is overproduced, it appears that leptin is necessary for its own downregulation. Leptin mRNA was also suppressed in adipose tissue of rats during a 16-hr fast and was rapidly induced during a 4-hr refeeding period. Insulin deficiency provoked by streptozotocin also markedly down-regulated leptin mRNA and this suppression was rapidly reversed by insulin. These results suggest that insulin may regulate the expression of leptin.

https://www.pnas.org/content/pnas/92/20/9034.full.pdf

Regulated expression of the obese gene product (leptin) in white adipose tissue and 3T3-L1 adipocytes.

Hormonal induction of 3T3-L1 preadipocytes triggers a cascade of events that initiate differentiation into adipocytes. CCAAT/enhancer-binding proteins beta and delta (C/EBPbeta/delta) are expressed early in the differentiation program, but are not immediately active. After a long lag, C/EBPbeta/delta become competent to bind to the C/EBP regulatory element in the C/EBPalpha gene promoter, C/EBPalpha being a transcriptional activator of numerous adipocyte genes. As C/EBPbeta/delta acquire binding activity, they become localized to centromeres as preadipocytes synchronously enter S phase at the onset of mitotic clonal expansion. Localization to centromeres occurs through C/EBP consensus-binding sites in centromeric satellite DNA. C/EBPalpha, which is antimitotic, becomes centromere-associated much later in the differentiation program as mitotic clonal expansion ceases and the cells become terminally differentiated.

/pdf/activation-and-centromeric-localization-of-ccaat-enhancer-1y4kput5fd.pdf

M D Lane

Papers

Leptin regulates proinflammatory immune responses

Regulation of Adipocyte Development

Differentiation-induced gene expression in 3T3-L1 preadipocytes: CCAAT/enhancer binding protein interacts with and activates the promoters of two adipocyte-specific genes.

Regulated expression of the obese gene product (leptin) in white adipose tissue and 3T3-L1 adipocytes.

Activation and centromeric localization of CCAAT/enhancer-binding proteins during the mitotic clonal expansion of adipocyte differentiation.