Summary Brown fat defends against hypothermia and obesity through thermogenesis mediated by mitochondrial UCP1. Recent data suggest that there are two distinct types of brown fat: classical brown fat derived from a myf-5 cellular lineage and UCP1-positive cells that emerge in white fat from a non-myf-5 lineage. Here we report the cloning of “beige” cells from murine white fat depots. Beige cells resemble white fat cells in having extremely low basal expression of UCP1, but like classical brown fat, they respond to cyclic AMP stimulation with high UCP1 expression and respiration rates. Beige cells have a gene expression pattern distinct from either white or brown fat and are preferentially sensitive to the polypeptide hormone irisin. Finally, we show that deposits of brown fat previously observed in adult humans are composed of beige adipose cells. These data illustrate a new cell type with therapeutic potential in mouse and human.

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Obesity and type 2 diabetes have been associated with a high-fat diet (HFD) and reduced mitochondrial mass and function. We hypothesized a HFD may affect expression of genes involved in mitochondrial function and biogenesis. To test this hypothesis, we fed 10 insulinsensitive males an isoenergetic HFD for 3 days with muscle biopsies before and after intervention. Oligonucleotide microarray analysis revealed 297 genes were differentially regulated by the HFD (Bonferonni adjusted P < 0.001). Six genes involved in oxidative phosphorylation (OXPHOS) decreased. Four were members of mitochondrial complex I: NDUFB3, NDUFB5, NDUFS1, and NDUFV1; one was SDHB in complex II and a mitochondrial carrier protein SLC25A12. Peroxisome proliferator-activated receptor ␥ coactivator-1 (PGC1) ␣ and PGC1␤ mRNA were decreased by ؊20%, P < 0.01, and ؊25%, P < 0.01, respectively. In a separate experiment, we fed C57Bl/6J mice a HFD for 3 weeks and found that the same OXPHOS and PGC1 mRNAs were downregulated by ϳ90%, cytochrome C and PGC1␣ protein by ϳ40%. Combined, these results suggest a mechanism whereby HFD downregulates genes necessary for OXPHOS and mitochondrial biogenesis. These changes mimic those observed in diabetes and insulin resistance and, if sustained, may result in mitochondrial dysfunction in the prediabetic/insulin-resistant state. Diabetes 54: 1926 -1933, 2005 A t the molecular and structural level, mitochondrial biogenesis and mitochondrial function are altered in diabetes, as well as in insulin-resistant relatives of type 2 diabetic subjects (1,2). At the ultra-structural level, a reduction in the number, location, and morphology of mitochondria is strongly associated with insulin resistance (1). Two recent microarray studies have shown that genes involved in oxidative phosphorylation (OXPHOS) exhibit reduced expression levels in the skeletal muscle of type 2 diabetic subjects and prediabetic subjects. These changes may be mediated by the peroxisome proliferator-activated receptor ␥ coactivator-1 (PGC1) pathway. PGC1␣-and PGC1␤-responsive OXPHOS genes show reduced expression in the muscle of patients with type 2 diabetes (3,4). In addition to the cellular energy sensor AMP kinase, the peroxisome proliferator-activated receptor cofactors PGC1␣ (5-7) and possibly PGC1␤ (8) activate mitochondrial biogenesis and increase OXPHOS gene expression by increasing the transcription, translation, and activation of the transcription factors necessary for mitochondrial DNA (mtDNA) replication. Similarly, PGC1␣ increases the transcription of enzymes necessary for substrate oxidation, electron transport, and ATP synthesis. Morphological and functional studies (1,9,10), combined with the recent microarray data, indicate that PGC1 is important in the development of type 2 diabetes.Rates of ATP synthesis, measured in situ with magnetic resonance spectroscopy, are decreased in subjects with a family history of diabetes before the onset of impaired glucose tolerance (2,10). Based on these results, the prevailing view is that these d...

Summary GDF15 is an established biomarker of cellular stress. The fact that it signals via a specific hindbrain receptor, GFRAL, and that mice lacking GDF15 manifest diet-induced obesity suggest that GDF15 may play a physiological role in energy balance. We performed experiments in humans, mice, and cells to determine if and how nutritional perturbations modify GDF15 expression. Circulating GDF15 levels manifest very modest changes in response to moderate caloric surpluses or deficits in mice or humans, differentiating it from classical intestinally derived satiety hormones and leptin. However, GDF15 levels do increase following sustained high-fat feeding or dietary amino acid imbalance in mice. We demonstrate that GDF15 expression is regulated by the integrated stress response and is induced in selected tissues in mice in these settings. Finally, we show that pharmacological GDF15 administration to mice can trigger conditioned taste aversion, suggesting that GDF15 may induce an aversive response to nutritional stress.

There is evidence from human twin and family studies as well as mouse and rat selection experiments that there are considerable interindividual differences in the response of cardiorespiratory fitness (CRF) and other cardiometabolic traits to a given exercise programme dose. We developed this consensus statement on exercise response variability following a symposium dedicated to this topic. There is strong evidence from both animal and human studies that exercise training doses lead to variable responses. A genetic component contributes to exercise training response variability.In this consensus statement, we (1) briefly review the literature on exercise response variability and the various sources of variations in CRF response to an exercise programme, (2) introduce the key research designs and corresponding statistical models with an emphasis on randomised controlled designs with or without multiple pretests and post-tests, crossover designs and repeated measures designs, (3) discuss advantages and disadvantages of multiple methods of categorising exercise response levels—a topic that is of particular interest for personalised exercise medicine and (4) outline approaches that may identify determinants and modifiers of CRF exercise response. We also summarise gaps in knowledge and recommend future research to better understand exercise response variability.