PGC1α is a co-activator involved in adaptive thermogenesis, fatty-acid oxidation and gluconeogenesis. We describe the identification of several isoforms of a new human PGC1α homologue, cloned independently and named PGC1β. The human PGC1β gene is localized to chromosome 5, has 13 exons and spans more than 78 kb. Two different 5′ and 3′ ends due to differential splicing were identified by rapid amplification of cDNA ends PCR and screening of human cDNA libraries. We show that PGC1β variants in humans, mice and rats are expressed predominantly in heart, brown adipose tissue, brain and skeletal muscle. PGC1β expression, unlike PGC1α, is not up-regulated in brown adipose tissue in response to cold or obesity. Fasting experiments showed that PGC1α, but not PGC1β, is induced in liver and this suggests that only PGC1α is involved in the hepatic gluconeogenesis. No changes in PGC1β gene expression were observed associated with exercise. Human PGC1β-1a and −2a isoforms localized to the cell nucleus and, specifically, the isoform PGC1β-1a co-activated peroxisome-proliferator-activated receptor-γ, -α and the thyroid hormone receptor β1. Finally, we show that ectopic expression PGC1β leads to increased mitochondrial number and basal oxygen consumption. These results suggest that PGC1β may play a role in constitutive adrenergic-independent mitochondrial biogenesis.
Abbreviations used: BAT, brown adipose tissue; CHO, Chinese-hamster ovary; DMEM, Dulbecco's modified Eagle's medium; FBS, foetal bovine serum; FCCP, carbonyl cyanide p-trifluoromethoxyphenylhydrazone; GFP, green fluorescent protein; GRE, glucocorticoid response element; HNF, hepatocyte nuclear factor; IRES, internal ribosomal entry; NR, nuclear receptor; NRF-1, nuclear respiratory factor 1; PERC, PGC1 (peroxisome-proliferator-activated receptor-γ co-activator 1)-related estrogen receptor co-activator; PPAR, peroxisome-proliferator-activated receptor; PRC, PGC-1-related co-activator; RACE, rapid amplification of cDNA ends; RPA, RNase protection assay; TEM, transmission electron microscopy; T3, 3,3′,5-tri-iodothyronine; TR, thyroid receptor; RXR, retinoid X receptor.
These authors have contributed equally to this work.