Playtime Prevents Obesity by Brain-Mediated Fat Browning
Authors: Kathleen J. Griffioen, Mark P. Mattson
Journal: Cell Metabolism (2011)

Laboratory animals usually become relatively insulin resistant and obese. In this issue of Cell Metabolism, Cao et al., 2011Cao L. Choi E.Y. Liu X. Martin A. Wang C. Xu X. During M.J. Cell Met. 2011; 14 (this issue): 324-338Abstract Full Text Full Text PDF PubMed Scopus (283) Google Scholar find that mice living in a complex environment are resistant to diet-induced obesity because they produce energy-dissipating brown fat cells within white fat depots, a process orchestrated by brain-derived neurotrophic factor. Laboratory animals usually become relatively insulin resistant and obese. In this issue of Cell Metabolism, Cao et al., 2011Cao L. Choi E.Y. Liu X. Martin A. Wang C. Xu X. During M.J. Cell Met. 2011; 14 (this issue): 324-338Abstract Full Text Full Text PDF PubMed Scopus (283) Google Scholar find that mice living in a complex environment are resistant to diet-induced obesity because they produce energy-dissipating brown fat cells within white fat depots, a process orchestrated by brain-derived neurotrophic factor. During development, white adipose (WA) cells may differentiate from progenitors located in the vasculature, whereas brown adipose (BA) cells arise from myogenic precursors (Laharrague and Casteilla, 2010Laharrague P. Casteilla L. Endocr. Dev. 2010; 19: 21-30Crossref PubMed Scopus (19) Google Scholar). In the adult, WA and BA cells can be generated from precursor cells; numbers of visceral WA cells increase in response to a positive energy balance, and new BA cells are generated in response to cold temperatures. Moreover, recent findings suggest that BA can exist within WA depots (Kozak, 2010Kozak L.P. Cell Metab. 2010; 11: 263-267Abstract Full Text Full Text PDF PubMed Scopus (186) Google Scholar). In this issue of Cell Metabolism, Cao et al., 2011Cao L. Choi E.Y. Liu X. Martin A. Wang C. Xu X. During M.J. Cell Met. 2011; 14 (this issue): 324-338Abstract Full Text Full Text PDF PubMed Scopus (283) Google Scholar report the remarkable finding that the “richness” of the living quarters of a mouse can determine the number of BA cells present within their WA depots and alter the vulnerability of the mice to diet-induced insulin resistance and obesity. Three-week-old male C57Bl/6 mice were housed (five mice per cage) either in usual laboratory cages containing only bedding material, or a playground-like enriched environment (EE) consisting of larger cages with running wheels, tunnels, huts, toys, a maze, and nesting material (all mice had free access to food and water). Four weeks later, inguinal, retroperitoneal, and epididymal WA fat pads were removed and were all found reduced in size by up to 70% compared to fat pads from mice in the control environment (Cao et al., 2011Cao L. Choi E.Y. Liu X. Martin A. Wang C. Xu X. During M.J. Cell Met. 2011; 14 (this issue): 324-338Abstract Full Text Full Text PDF PubMed Scopus (283) Google Scholar). The reduction in WA levels could not be accounted for simply by more exercise in the EE, because mice provided running wheels in standard cages exercised more than mice in the EE but exhibited less reduction of WA. Interestingly, the EE mice exhibited increased food intake and elevated resting oxygen consumption at thermoneutrality. In addition, oxygen consumption was elevated in WA isolated from the EE mice, whereas running mice exhibited higher oxygen consumption in BA. Clusters of cells that expressed markers of BA, including PRDM16, PGC-1α, and UCP1, were present within the WA depots of EE mice (Figure 1). Brain-derived neurotrophic factor (BDNF) has emerged a as a key mediator of the effects of a range of environmental challenges on the structure and function of neuronal circuits involved in cognition, autonomic functions, and energy metabolism (Lu et al., 2008Lu Y. Christian K. Lu B. Neurobiol. Learn. Mem. 2008; 89: 312-323Crossref PubMed Scopus (577) Google Scholar, Mattson and Wan, 2008Mattson M.P. Wan R. Neuromolecular Med. 2008; 10: 157-168Crossref PubMed Scopus (19) Google Scholar, Noble et al., 2011Noble E.E. Billington C.J. Kotz C.M. Wang C. Am. J. Physiol. Regul. Integr. Comp. Physiol. 2011; 300: R1053-R1069Crossref PubMed Scopus (218) Google Scholar). Recent findings suggest that increased expression of BDNF in the brain may also mediate beneficial effects of dietary energy restriction and exercise on body weight and glucose metabolism (Duan et al., 2003Duan W. Guo Z. Jiang H. Ware M. Mattson M.P. Endocrinology. 2003; 144: 2446-2453Crossref PubMed Scopus (151) Google Scholar, Pedersen et al., 2009Pedersen B.K. Pedersen M. Krabbe K.S. Bruunsgaard H. Matthews V.B. Febbraio M.A. Exp. Physiol. 2009; 94: 1153-1160Crossref PubMed Scopus (179) Google Scholar). Animals in EEs exhibit elevated BDNF levels in multiple brain regions, and Cao et al., 2011Cao L. Choi E.Y. Liu X. Martin A. Wang C. Xu X. During M.J. Cell Met. 2011; 14 (this issue): 324-338Abstract Full Text Full Text PDF PubMed Scopus (283) Google Scholar found that selective overexpression of BDNF in the hypothalamus mimicked, whereas inhibition of BDNF receptor (trkB) signaling counteracted, the effects of EE on adiposity and generation of BA-like cells in WA depots. Additional experiments in which β-adrenergic receptor signaling was manipulated pharmacologically suggested that sympathetic nervous system (SNS) activation mediated the EE-induced “browning” of WA (Figure 1). Several questions arise from the revelation of an exercise-independent process by which living in a playground-like domicile promotes a lean, energy-dissipating body. (1) Cao et al., 2011Cao L. Choi E.Y. Liu X. Martin A. Wang C. Xu X. During M.J. Cell Met. 2011; 14 (this issue): 324-338Abstract Full Text Full Text PDF PubMed Scopus (283) Google Scholar performed their experiments only on juvenile mice. Because the ability of neurons to upregulate BDNF expression in response to environmental signals may decline during aging (Arumugam et al., 2010Arumugam T.V. Phillips T.M. Cheng A. Morrell C.H. Mattson M.P. Wan R. Ann. Neurol. 2010; 67: 41-52Crossref PubMed Scopus (193) Google Scholar), it will be important to determine if EE is effective in stimulating the formation of BA cells throughout life. (2) Would more limited periods of exposure to an EE (e.g., for a few hours each day, or every other day) be sufficient to reduce WA, increase BA, and counteract an obesogenic diet? (3) What are the differences in the neuronal circuits activated by exercise and living in an EE that account for their differential effects on the autonomic nervous system and adipose cell biology? Perhaps the EE stimulates pathways that enhance BDNF signaling in SNS-linked hypothalamic nuclei by a greater amount than in other brain regions such as the hippocampus. (4) What, if any, is the evolutionary advantage of reducing energy stores and increasing thermogenesis when living in a complex environment versus a more mundane environment? Such a response to an EE might be beneficial only when food is readily available, as in the study of Cao et al., 2011Cao L. Choi E.Y. Liu X. Martin A. Wang C. Xu X. During M.J. Cell Met. 2011; 14 (this issue): 324-338Abstract Full Text Full Text PDF PubMed Scopus (283) Google Scholar or in herbivores in a wild environment where eluding predators is critical for survival (Martin et al., 2010Martin B. Maudsley S. Mattson M.P. Proc. Natl. Acad. Sci. USA. 2010; 107: 6127-6133Crossref PubMed Scopus (263) Google Scholar). Future experiments could elucidate this issue by studying the interactions of dietary energy restriction and EEs on adipose tissues. (5) Finally, how does the WA “browning” in this study translate to a truly “wild-type” environment? Laboratory animals are housed in an unnaturally inactive and monotonous environment and may better represent an obese cohort (Martin et al., 2010Martin B. Maudsley S. Mattson M.P. Proc. Natl. Acad. Sci. USA. 2010; 107: 6127-6133Crossref PubMed Scopus (263) Google Scholar). Therefore, does the WA browning described by Cao et al., 2011Cao L. Choi E.Y. Liu X. Martin A. Wang C. Xu X. During M.J. Cell Met. 2011; 14 (this issue): 324-338Abstract Full Text Full Text PDF PubMed Scopus (283) Google Scholar reflect a shift toward improved energy metabolism in normal subjects, or rather a shift away from obesity to a healthy state? Although it remains to be determined whether the adipose phenotype of humans can be sculpted by interactions with environmental “playthings,” the new findings are provocative (Cao et al., 2011Cao L. Choi E.Y. Liu X. Martin A. Wang C. Xu X. During M.J. Cell Met. 2011; 14 (this issue): 324-338Abstract Full Text Full Text PDF PubMed Scopus (283) Google Scholar). There is ample evidence that individuals whose lifestyle includes a cognitively engaging career path and a variety of hobbies tend to be healthier than those who are less engaged (Andersen et al., 1999Andersen R.E. Wadden T.A. Bartlett S.J. Zemel B. Verde T.J. Franckowiak S.C. JAMA. 1999; 281: 335-340Crossref PubMed Scopus (531) Google Scholar). It will be important to determine the extent to which health can be improved by promoting enriched environments in children and adults, and by developing novel interventions that target the cellular and molecular pathways stimulated by EEs. White to Brown Fat Phenotypic Switch Induced by Genetic and Environmental Activation of a Hypothalamic-Adipocyte AxisCao et al.Cell MetabolismSeptember 07, 2011In BriefLiving in an enriched environment with complex physical and social stimulation leads to improved cognitive and metabolic health. In white fat, enrichment induced the upregulation of the brown fat cell fate determining gene Prdm16, brown fat-specific markers, and genes involved in thermogenesis and β-adrenergic signaling. Moreover, pockets of cells with prototypical brown fat morphology and high UCP1 levels were observed in the white fat of enriched mice associated with resistance to diet-induced obesity. Full-Text PDF Open Archive