Brown adipose tissue thermogenesis and obesity

Himms‐Hagen, Jean

doi:10.1016/0163-7827(89)90009-x

Cited by 315 publications

(201 citation statements)

References 410 publications

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“…Nonshivering thermogenesis in BAT contributes significantly to resting energy expenditure in rodents. 19,20 Increased thermogenic activity of BAT, as assessed by GDP binding, has been demonstrated in cancer cachexia models. 21,22 Our results suggested that inappropriate increased energy expenditure in BAT was associated with uremia-associated cachexia.…”

Section: Discussionmentioning

confidence: 99%

Peripheral Administration of the Melanocortin-4 Receptor Antagonist NBI-12i Ameliorates Uremia-Associated Cachexia in Mice

Cheung

Kuo

Markison

et al. 2007

Journal of the American Society of Nephrology

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We have recently shown that genetic or pharmacological blockade of the melanocortin-4 receptor (MC4-R) attenuates uremia-associated cachexia. However, the potential clinical utility of this approach has been limited by the need to deliver a peptide MC4-R antagonist into the ventricles of the brain. NBI-12i is a recently developed small molecule MC4-R antagonist, with high affinity and selectivity that penetrates the central nervous system after peripheral administration. We tested whether NBI-12i would also be effective in attenuating uremia-associated cachexia in a mouse model. Intraperitoneal administration of NBI-12i stimulated food intake and weight gain in uremic mice. Furthermore, NBI-12i-treated uremic mice gained lean body mass, fat mass, and had a lower basal metabolic rate compared to vehicle-treated and diet-supplemented uremic mice, which lost both lean body mass and fat mass and had an increase in basal metabolic rate. We found that NBI-12i normalizes the expression of uncoupling protein, which is normally upregulated in uremic mice, and we speculate that this may contribute to the drug's protective effect. These data underscore the importance of melanocortin signaling in the pathogenesis of uremia-associated cachexia and demonstrate the potential of peripheral administration of MC4-R antagonists as a novel therapeutic approach.

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Section: Discussionmentioning

confidence: 99%

Peripheral Administration of the Melanocortin-4 Receptor Antagonist NBI-12i Ameliorates Uremia-Associated Cachexia in Mice

Cheung

Kuo

Markison

et al. 2007

Journal of the American Society of Nephrology

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“…7,49 It is, however, not the aim of this paper to cover extensively EE regulatory systems, and readers can refer to several papers that have been written on the topic. 5,42,[48][49][50][51][52][53][54][55] Similarly, cellular mechanisms on the basis of human body thermogenesis, such as mitochondrial adenosine triphosphate synthesis efficiency, 56,57 uncoupling proteins 53,58 and their related increased muscle efficiency 59 will not be covered in this paper, as they have been directly addressed in their respective cited references. This conceptual paper will rather describe three conditions that have been associated to adaptive thermogenesis and that may thus represent limiting factors in weight loss, and confer a significant susceptibility to weight gain/regain in some individuals: body weight loss and regain cycles, organochlorine plasma concentration and hypoxia in severe form of obstructive sleep apnea.…”

Section: Determinant Factors Associated With the Adaptive Thermogenesismentioning

confidence: 99%

Clinical significance of adaptive thermogenesis

et al. 2007

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The epidemic of obesity is developing faster than the scientific understanding of an efficient way to overcome it, as reflected by the low success rate of short-and long-term weight loss interventions. From a clinical standpoint, this suggests that the body tends to defend a set point of possible genetic origin in the context of a weight-reducing program. As described in this paper, this limited therapeutic success may depend on adaptive thermogenesis, which represents in this case the decrease in energy expenditure (EE) beyond what could be predicted from the changes in fat mass or fat-free mass under conditions of standardized physical activity in response to a decrease in energy intake. This issue has been documented in recent studies that have shown in obese individuals adhering to a weight reduction program a greater than predicted decrease in EE, which in some cases was quantitatively sufficient to overcome the prescribed energy restriction, suggesting a role for adaptive thermogenesis in unsuccessful weight loss interventions and reduced body weight maintenance. As also discussed in this paper, this 'adaptive thermogenesis' can be influenced by environmental factors, which have not been frequently considered up to now. This is potentially the case for plasma organochlorine concentration and oxygen desaturation in obstructive sleep apnea syndrome. It is concluded that health professionals should be aware that in some vulnerable individuals, adaptive thermogenesis can be multicausal, and has the capacity to compensate, at least partly, for the prescribed energy deficit, possibly going beyond any good compliance of some patients.

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“…In contrast, transgenic overexpression of human β1-AR (also known as ADRB1) in WAT resulted in lean mice and an abundance of brown adipocytes in WAT [22]. 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].…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2008

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Aims/hypothesis Proinflammatory cytokines, including IL-1, exert pleiotropic effects on the neuro-immuno-endocrine system. Previously, we showed that mice with knockout of the gene encoding IL-1 receptor antagonist (Il1ra −/− , also known as Il1rn −/− ) have a lean phenotype. The present study was designed to analyse the mechanisms leading to this lean phenotype.Methods Il1ra −/− mice were fed a high-fat diet following weaning. Energy expenditure, body temperature, heart rate, blood parameters, urinary catecholamines and adipose tissue were analysed. Results Il1ra −/− mice exhibited resistance to obesity induced by a high-fat diet; this resistance was associated with increased energy expenditure and a decreased respiratory quotient, indicating that the ratio of fat:carbohydrate metabolism in Il1ra −/− mice is greater than in controls. Activity level in Il1ra −/− mice was significantly decreased and body temperature was significantly increased, compared with wild-type (WT) mice. Inguinal white adipose tissues in Il1ra −/− mice express increased levels of Ucp1 and mitochondrial respiratory chain genes compared with WT mice. Histological analysis of adipose tissue in Il1ra −/− mice revealed that brown adipose tissue is hyperactive and inguinal white adipose tissue contains smaller cells, which exhibit the distinctive multilocular appearance of brown adipocytes. Urinary epinephrine and norepinephrine excretion in Il1ra −/− mice was significantly increased compared with WT mice, suggesting that Il1ra −/− mice have increased sympathetic tone. Consistent with this, heart rate in Il1ra −/− mice was also significantly increased. Conclusions/interpretation Our results show that Il1ra −/− mice have increased energy expenditure, fat:carbohydrate oxidation ratio, body temperature, heart rate and catecholamine production. All of these observations are consistent with an enhanced sympathetic tone.

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Brown adipose tissue thermogenesis and obesity

Cited by 315 publications

References 410 publications

Peripheral Administration of the Melanocortin-4 Receptor Antagonist NBI-12i Ameliorates Uremia-Associated Cachexia in Mice

Peripheral Administration of the Melanocortin-4 Receptor Antagonist NBI-12i Ameliorates Uremia-Associated Cachexia in Mice

Clinical significance of adaptive thermogenesis

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

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