Independent and Additive Effects of Central POMC and Leptin Pathways on Murine Obesity

Boston, Bruce A.; Blaydon, Kathryn M.; Varnerin, Jeffrey P.; Cone, Roger D.

doi:10.1126/science.278.5343.1641

Cited by 229 publications

(143 citation statements)

References 22 publications

(2 reference statements)

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“…Interestingly, if these mice are also made leptin de®cient by introducing the ob gene, they become even more obese, but are then sensitive to leptin. 23 This is easily explained as the leptin system is now operating from a zero baseline.…”

Section: Insights From Rodentsmentioning

confidence: 99%

Leptin resistance in obese humans: does it exist and what does it mean?

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Trayhurn³

1998

Int J Obes

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Section: Insights From Rodentsmentioning

confidence: 99%

Leptin resistance in obese humans: does it exist and what does it mean?

Arch

Stock

Trayhurn³

1998

Int J Obes

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“…By using a double mutant combining [Lep.sup.ob/ob] with the gene knockout [Npy.sup.-/-], it was shown that there are parallel pathways for leptin-related appetite control in the hypothalamus (Erickson et al 1996). (Boston et al 1997). Not all obesity is mediated by the leptin loop (Schonfeld-Warden & Warden 1997), not all leptin effects are mediated by appetite changes (Yu et al 1997), and diabetic symptoms are not joined inexorably with obesity (Hotamisligil et al 1996).…”

Section: Genetic Dissectionmentioning

confidence: 99%

Single-Gene Influences on Brain and Behavior

Wahłsten

1999

Annu. Rev. Psychol.

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Abstract:As traditional behavioral genetics analysis merges with neurogenetics, the field of neurobehavioral genetics, focusing on single-gene effects, comes into being. New biotechnology has greatly accelerated gene discovery and the study of gene function in relation to brain and behavior. More than 7,000 genes in mice and 10,000 in humans have now been documented, and extensive information about the genetics of several species is readily available on the World Wide Web. Based on knowledge of the DNA sequence of a gene, a targeted mutation with the capacity to disable it can be created. These knockouts--also called null mutants--are employed in the study of a wide range of phenotypes, including learning and memory, appetite and obesity, and circadian rhythms. The era of examining single-gene effects from a reductionistic perspective is waning, and research with interacting arrays of genes in various environmental contexts is demonstrating a need for systems-oriented theory.

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“…Indeed, it is now clear that leptin-independent melanocortinergic CNS pathways exist. [103][104][105] Nonetheless, it is clearly established that a-MSH acting through MC4-Rs is a fundamental regulator of coordinated energy homeostasis. Key questions that remain include what metabolic and neural cues, beside leptin, drive the melanocortinergic neural circuits.…”

mentioning

confidence: 99%

“…As noted, leptin-independent melanocortinergic pathways also exist. [103][104][105] Therefore, our laboratory has recently tested the extent to which Arc POMC neurons contribute to CNS leptin signaling by using the Cre/loxP system. 103 First, transgenic mice expressing Cre in POMC neurons (POMC-Cre mice) were generated by using a POMC bacterial artificial chromosome.…”

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confidence: 99%

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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Independent and Additive Effects of Central POMC and Leptin Pathways on Murine Obesity

Cited by 229 publications

References 22 publications

Leptin resistance in obese humans: does it exist and what does it mean?

Leptin resistance in obese humans: does it exist and what does it mean?

Single-Gene Influences on Brain and Behavior

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

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