| Leptin is an adipocyte derived hormone that negatively regulates body mass and food intake. ob/ob mice which carry leptin mutations are obese, hyperphagic, and manifest a number of neuroendocrine abnormalities characteristic of starvation. In contrast, high leptin levels produced by exogenous hormone administration signal that excess energy stores are present and in turn reduce food intake and body mass. These findings indicate that dynamic alterations in leptin levels affect metabolic and physiologic processes that either expand (in the case of low leptin) or contract (in the case of high leptin) body energy stores.;Oligonucleotide microarrays were used to characterize the molecular events in white adipose tissue which are associated with alterations in circulating leptin levels. The conclusions form these studies are as follows: (1) A large number of metabolic, inflammatory, acute phase, and structural genes are dysregulated by genetic leptin deficiency of the ob/ ob mouse. (2) Groups of genes are specifically altered by high levels of leptin when compared to simple food restriction in control animals. This response includes a potent repression of the entire pathway of genes responsible for de-novo fatty acid synthesis as well as their master transcriptional regulator SREBP-1, consistent with the ability of increased circulating leptin levels to selectively reduce adiposity. (3) Low levels of circulating leptin in lean mice produce a rapid expansion of fat mass. This is heralded by massive transient accumulation of adipocyte glycogen followed by transcriptional upregulation of the enzymatic cascade necessary to convert this glycogen into acetyl-CoA and glycerol, the principle substrates for triglyceride synthesis. (4) Adipocyte specific gene expression is maintained in the same total numbers of adipocytes during long term leptin treatment. These adipocytes are, however, largely devoid of triglyceride content and are marked by upregulation of a novel cytokine signaling event.;These data indicate that dynamic alterations in leptin level have pronounced effects on the molecular phenotype of white adipose tissue. The leptin-regulated patterns of gene expression that are described provide markers for the unique physiologic response to leptin, and explain, in part, the ability of leptin to potently and selectively modulate the size of adipose tissue mass. |
