Obesity and the Regulation of Energy Balance

Spiegelman, Bruce M.; Flier, Jeffrey S.

doi:10.1016/s0092-8674(01)00240-9

Cited by 2,170 publications

(1,684 citation statements)

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“…Increased energy expenditure and decreased respiratory quotient in Il1ra −/− mice The markedly reduced weight of HFD-fed Il1ra −/− mice suggests that they may have either reduced food intake and/or increased energy expenditure [12]. Food intake per mouse was significantly decreased in Il1ra −/− mice, while food intake normalised to body weight was not significantly different between WT and Il1ra −/− mice that were fed a HFD (ESM Fig.…”

Section: Resultsmentioning

confidence: 97%

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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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Section: Resultsmentioning

confidence: 97%

“…Energy expenditure represents the sum of the total energy needed for maintaining normal cell and organ function, metabolism, physical activity and facultative (adaptive) thermogenesis [12]. The sympathetic nervous system (SNS) is thought to be critical for the prevention of obesity associated with a high-fat diet (HFD) [13].…”

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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“…[166][167][168] Moreover, by using the MC4-R/GFP mice line, we identified MC4-R-positive cells coexpressing Y1-R mRNA in these forebrain sites that receive both NPY and melanocortinergic inputs. 80,107,149,150 Consequently, relevant to current discussions, 15,23 we hypothesize that the convergence of leptin/melanocortin and NPY signaling pathways likely contributes to their counterpoised relationship in energy balance regulation (Figure 4). …”

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confidence: 92%

“…[8][9][10][11][12][13][14] In the current review, we will illustrate the neuroanatomic and molecular genetic aspects of the melanocortin and neuropeptide Y (NPY) systems residing in the CNS downstream of leptin and ghrelin, to discuss the neural bases of feeding, metabolism, and emotion. Additionally, we point the reader to recent reviews for other critical CNS systems regulating food intake and body weight, including those by Barsh and Schwartz, 15 Elmquist et al, 16 Friedman and Halaas, 17 Friedman, 1 Grill and Kaplan, 18 O'Rahilly et al, 19 Saper et al, 20 Sawchenko, 21 Schwartz et al, 22 Spiegelman and Flier, 23 van den Pol, 24 Woods et al, 25 Zigman and Elmquist. 26 Anatomic and molecular bases for metabolic/autonomic control of body weight…”

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confidence: 94%

Body weight is regulated by the brain: a link between feeding and emotion

2005

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Regulated energy homeostasis is fundamental for maintaining life. Unfortunately, this critical process is affected in a high number of mentally ill patients. Eating disorders such as anorexia nervosa are prevalent in modern societies. Impaired appetite and weight loss are common in patients with depression. In addition, the use of neuroleptics frequently produces obesity and diabetes mellitus. However, the neural mechanisms underlying the pathophysiology of these behavioral and metabolic conditions are largely unknown. In this review, we first concentrate on the established brain machinery of food intake and body weight, especially on the melanocortin and neuropeptide Y (NPY) systems as illustration. These systems play a critical role in receiving and processing critical peripheral metabolic cues such as leptin and ghrelin. It is also notable that both systems modulate emotion and motivated behavior as well. Secondly, we discuss the significance and potential promise of multidisciplinary molecular and neuroanatomic techniques that will likely increase the understanding of brain circuitries coordinating energy homeostasis and emotion. Finally, we introduce several lines of evidence suggesting a link between the melanocortin/NPY systems and several neurotransmitter systems on which many of the psychotropic agents exert their influence. Maintaining energy homeostasis is fundamental for survival. However, obesity due to over-nutrition is an increasing worldwide public health problem. 1 In psychiatric practice, on the other hand, impaired appetite is one of the crucial issues. Anorexia and weight loss are common, for example, in patients suffering from depression. Eating disorders are medically intractable and life threatening. In addition, the so-called 'atypical' antipsychotic agents, currently and widely used to treat psychoses, often induce hyperphagia, obesity, and diabetes mellitus. [2][3][4] In the past decade, fortunately, there has been remarkable progress in understanding the molecular mechanisms of food intake and body weight. This is due in large part to increased research activity towards combating the rising incidences of obesity and associated metabolic disorders. As a result, it is now established that the central nervous system (CNS) senses and processes peripheral metabolic cues including leptin 5 and ghrelin, 6,7 resulting in coordinated energy homeostasis. However, the pathophysiology of the disequilibrium between energy intake and expenditure in psychiatric disorders remains largely unknown. Nevertheless, evidence suggests that several CNS systems regulating energy balance may be dysregulated in patients with mental illnesses, for example, eating disorders, and drug addiction. [8][9][10][11][12][13][14] In the current review, we will illustrate the neuroanatomic and molecular genetic aspects of the melanocortin and neuropeptide Y (NPY) systems residing in the CNS downstream of leptin and ghrelin, to discuss the neural bases of feeding, metabolism, and emotion. Additionally, we point the reader to...

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“…Adipocytes are specialized cells that play an essential role in the regulation of energy homeostasis [Spiegelman and Flier, 2001;Kershaw and Flier, 2004]. However, the excessive accumulation or increased size of adipocytes can result in obesity and its associated disease sequelae [Visscher and Seidell, 2001].…”

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confidence: 99%

Prostaglandin F2α inhibits adipocyte differentiation via a Gαq‐Calcium‐Calcineurin‐Dependent signaling pathway

Liu

Clipstone

2006

J of Cellular Biochemistry

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Prostaglandin F2a (PGF2a) is a potent physiological inhibitor of adipocyte differentiation, however the specific signaling pathways and molecular mechanisms involved in mediating its anti-adipogenic effects are not well understood. In the current study, we now provide evidence that PGF2a inhibits adipocyte differentiation via a signaling pathway that requires heterotrimeric G-protein Gaq subunits, the elevation of the intracellular calcium concentration ([Ca 2þ ] i ), and the activation of the Ca 2þ /calmodulin-regulated serine/threonine phosphatase calcineurin. We show that while this pathway acts to inhibit an early step in the adipogenic cascade, it does not interfere with the initial mitotic clonal expansion phase of adipogenesis, nor does it affect either the expression, DNA binding activity or differentiation-induced phosphorylation of the early transcription factor C/EBPb. Instead, we find that PGF2a inhibits adipocyte differentiation via a calcineurin-dependent mechanism that acts to prevent the expression of the critical pro-adipogenic transcription factors PPARg and C/EBPa. Furthermore, we demonstrate that the inhibitory effects of PGF2a on both the expression of PPARg and C/EBPa and subsequent adipogenesis can be attenuated by treatment of preadipocytes with the histone deacetylase (HDAC) inhibitor trichostatin A. Taken together, these results indicate that PGF2a inhibits adipocyte differentiation via a Gaq-Ca 2þ -calcineurin-dependent signaling pathway that acts to block expression of PPARg and C/EBPa by a mechanism that appears to involves an HDAC-sensitive step.

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Obesity and the Regulation of Energy Balance

Cited by 2,170 publications

References 93 publications

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

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

Body weight is regulated by the brain: a link between feeding and emotion

Prostaglandin F2α inhibits adipocyte differentiation via a Gαq‐Calcium‐Calcineurin‐Dependent signaling pathway

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