UCP1: the only protein able to mediate adaptive non-shivering thermogenesis and metabolic inefficiency

Abstract

The uniqueness of UCP1 (as compared to UCP2/UCP3) is evident from expression analysis and ablation studies. UCP1 expression is positively correlated with metabolic inefficiency, being increased by cold acclimation (in adults or perinatally) and overfeeding, and reduced in fasting and genetic obesity. Such a simple relationship is not observable for UCP2/UCP3. Studies with UCP1-ablated animals substantiate the unique role of UCP1: the phenomenon of adaptive adrenergic non-shivering thermogenesis in the intact animal is fully dependent on the presence of UCP1, and so is any kind of cold acclimation-recruited non-shivering thermogenesis; thus UCP2/UCP3 (or any other proteins or metabolic processes) cannot substitute for UCP1 physiologically, irrespective of their demonstrated ability to show uncoupling in reconstituted systems or when ectopically expressed. Norepinephrine-induced thermogenesis in brown-fat cells is absolutely dependent on UCP1, as is the uncoupled state and the recoupling by purine nucleotides in isolated brown-fat mitochondria. Although very high UCP2/UCP3 mRNA levels are observed in brown adipose tissue of UCP1-ablated mice, there is no indication that the isolated brown-fat mitochondria are uncoupled; thus, high expression of UCP2/UCP3 does not necessarily confer to the mitochondria of a tissue a propensity for being innately uncoupled. Whereas the thermogenic effect of fatty acids in brown-fat cells is fully UCP1-dependent, this is not the case in brown-fat mitochondria; this adds complexity to the issues concerning the mechanisms of UCP1 function and the pathway from beta(3)-adrenoceptor stimulation to UCP1 activation and thermogenesis. In addition to amino acid sequences conserved in all UCPs as part of the tripartite structure, all UCPs contain certain residues associated with nucleotide binding. However, conserved amongst all UCP1s so far sequenced, and without parallel in all UCP2/UCP3, are two sequences: 144SHLHGIKP and the C-terminal sequence RQTVDC(A/T)T; these sequences may therefore be essential for the unique thermogenic function of UCP1. The level of UCP1 in the organism is basically regulated at the transcriptional level (physiologically probably mainly through the beta(3)-adrenoceptor/CREB pathway), with influences from UCP1 mRNA stability and from the delay caused by translation. It is concluded that UCP1 is unique amongst the uncoupling proteins and is the only protein able to mediate adaptive non-shivering thermogenesis and the ensuing metabolic inefficiency.

Increased fat:carbohydrate oxidation ratio in Il1ra −/− mice on a high-fat diet is associated with increased sympathetic tone

“…Brown and white adipocytes are usually located in distinct depots and can be distinguished morphologically [23]; brown adipocytes contain multilocular lipid vacuoles and numerous mitochondria, whereas white adipocytes have a unilocular lipid vacuole and few mitochondria. UCP-1 is specifically produced in BAT; this protein uncouples oxidative phosphorylation from electron transport, resulting in the dissipation of energy as heat [24,25]. The emergence of these ectopic cells in the WAT of rats [26] and of mice [27] was found to be induced by cold acclimatisation or by the administration of selective β3-AR agonists [27,28].…”

Carnitine is necessary to maintain the phenotype and function of brown adipose tissue

“…1 UCP-1 localizes to the mitochondrial inner membrane and uncouples proton entry from ATP synthesis. 1,2 Previous studies have reported that decreased expression of UCP-1 caused by various conditions such as fasting, deletion of the UCP-1 gene, and obesity (eg, ob/ob and db/db mice) induces a low body temperature resulting from the impaired thermogenesis in BAT. [3][4][5][6][7][8] Carnitine has been widely distributed in various tissues and organs throughout the body, including BAT, and it has an essential role in the transfer of long-chain fatty acids into the mitochondria for b-oxidation.…”

Promotion of lipid storage rather than of thermogenic competence by fetal versus newborn calf serum in primary cultures of brown adipocytes

“…Type 2 deiodinase ( Dio2 ) 29 displayed less batch-to-batch variability and was overall expressed at higher levels in cells differentiated in the presence of FBS compared to NCS (Figure 2IJ). The main functional gene of brown adipocyte function, Uncoupling protein-1 ( Ucp1 ), 30,31 displayed rather wide variation in expression between different batches of each serum type (Figure 2K). However, no consistent difference between FBS and NCS on basal Ucp1 expression was observed (Figure 2L).…”