Activation of melanocortin-4-receptors (MC4Rs) reduces body fat stores by decreasing food intake and increasing energy expenditure. MC4Rs are expressed in multiple CNS sites, any number of which could mediate these effects. To identify the functionally relevant sites of MC4R expression, we generated a loxP-modified, null Mc4r allele (loxTB Mc4r) that can be reactivated by Cre-recombinase. Mice homozygous for the loxTB Mc4r allele do not express MC4Rs and are markedly obese. Restoration of MC4R expression in the paraventricular hypothalamus (PVH) and a subpopulation of amygdala neurons, using Sim1-Cre transgenic mice, prevented 60% of the obesity. Of note, increased food intake, typical of Mc4r null mice, was completely rescued while reduced energy expenditure was unaffected. These findings demonstrate that MC4Rs in the PVH and/or the amygdala control food intake but that MC4Rs elsewhere control energy expenditure. Disassociation of food intake and energy expenditure reveals unexpected divergence in melanocortin pathways controlling energy balance.

MicroRNAs (miRNAs) have within the past decade emerged as key regulators of metabolic homoeostasis. Major tissues in intermediary metabolism important during development of the metabolic syndrome, such as β‐cells, liver, skeletal and heart muscle as well as adipose tissue, have all been shown to be affected by miRNAs. In the pancreatic β‐cell, a number of miRNAs are important in maintaining the balance between differentiation and proliferation (miR‐200 and miR‐29 families) and insulin exocytosis in the differentiated state is controlled by miR‐7, miR‐375 and miR‐335. MiR‐33a and MiR‐33b play crucial roles in cholesterol and lipid metabolism, whereas miR‐103 and miR‐107 regulates hepatic insulin sensitivity. In muscle tissue, a defined number of miRNAs (miR‐1, miR‐133, miR‐206) control myofibre type switch and induce myogenic differentiation programmes. Similarly, in adipose tissue, a defined number of miRNAs control white to brown adipocyte conversion or differentiation (miR‐365, miR‐133, miR‐455). The discovery of circulating miRNAs in exosomes emphasizes their importance as both endocrine signalling molecules and potentially disease markers. Their dysregulation in metabolic diseases, such as obesity, type 2 diabetes and atherosclerosis stresses their potential as therapeutic targets. This review emphasizes current ideas and controversies within miRNA research in metabolism.

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An enormous amount of data has been collected on the uncoupling proteins 2 and ±3 (UCP2 and ±3) since their discovery in 1997 and well over 400 publications with either UCP2 or UCP3 or both as a keyword currently exist in public bibliographic databases. This is the equivalent of two new papers a week on the subject during the last four years, and that is excluding those papers on UCP1 alone. Despite the intense focus on these proteins their function and role in metabolism is not clear. There have been numerous clues to the possible functions of these proteins, and many theories have been offered but it is still not known what these uncoupling protein homologues actually do [1±6]. Mitochondrial bioenergetics in briefThe mitochondrial oxidation of substrates results in reduced NADH and FADH 2 , which deliver their electrons to the electron transport chain in the inner mitochondrial membrane. The chemiosmotic hypothesis proposes that oxidation is coupled by the elec- AbstractUncoupling proteins are mitochondrial carrier proteins which are able to dissipate the proton gradient of the inner mitochondrial membrane. This uncoupling process reduces the amount of ATP generated through an oxidation of fuels. The hypothesis that uncoupling proteins (UCPs) are candidate genes for human obesity or Type II (non-insulin-dependent) diabetes mellitus is based on the finding that a chemical uncoupling of the mitochondrial membrane reduces body adiposity, and that lower metabolic rates predict weight gain. It is straightforward to hypothesize that common polymorphisms of UCP1, UCP2 and UCP3 genes lower metabolic rate by a more efficient energy coupling in the mitochondria. Furthermore, genetically engineered mice over expressing different UCP homologues are lean and resistant to diet-induced obesity. The three uncoupling protein homologue genes UCP1, UCP2, and UCP3 have been investigated for polymorphisms and mutations and their impact on Type II diabetes mellitus, obesity, and body weight gain or BMI. The main conclusion is that variation in the UCP1, UCP2 or UCP3 genes is not associated with major alterations of body weight gain. The contribution of UCP genes towards polygenic obesity and Type II diabetes is evaluated and discussed. [Diabetologia (2001) Corresponding author: Oluf Pedersen, MD, DMSc, Steno Diabetes Center, Niels Steensens Vej 2, DK-2820 Gentofte, Denmark, E-mail: olufp@dadlnet.dk Abbreviations: UCP, Uncoupling protein; RMR, resting metabolic rate; BMR, basal metabolic rate; BAT, brown adipose tissue: ROS, reactive oxygen species; BMCP1, brain mitochondrial carrier protein 1; WAT, white adipose tissue; skm, skeletal muscle; LPS, lipopolysaccharide; PPAR, peroxisome proliferator activated receptor; 24h-EE, 24 hours energy expenditure; b3-AR, beta 3 adrenergic receptor; UTR, untranslated region; SMR, sleeping metabolic rate