Hypothalamic bHLH transcription factors are novel candidates in the regulation of energy balance

Nilaweera, Kanishka N.; Ellis, Claire; Barrett, Perry; Mercer, Julian G.; Morgan, Peter J.

doi:10.1046/j.1460-9568.2002.01894.x

Cited by 32 publications

(28 citation statements)

References 36 publications

(44 reference statements)

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“…All these regions also express Mc4r (23). Previous studies that did not report Sim1 expression outside the PVN and SON used less sensitive in situ hybridization techniques or examined only fetal or newborn mice (22,25). We propose that, in Sim1ϩ/Ϫ adults, dysfunction of Sim1-expressing neurons in the PVN, LHA, or amygdala, rather than their absence, causes hyperphagia and obesity.…”

Section: Discussionmentioning

confidence: 83%

Sim1 gene dosage modulates the homeostatic feeding response to increased dietary fat in mice

Holder

Zhang

Kublaoui

et al. 2004

American Journal of Physiology-Endocrinology and Metabolism

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. Sim1 gene dosage modulates the homeostatic feeding response to increased dietary fat in mice. Am J Physiol Endocrinol Metab 287: E105-E113, 2004. First published February 24, 2004 10.1152/ajpendo.00446.2003.-Haploinsufficiency of the transcription factor gene Sim1 has been previously implicated in hyperphagic obesity in humans and mice. To investigate the relation between Sim1 dosage and hyperphagia, we generated sim1-knockout mice and studied their growth and feeding behavior. Heterozygous mice weaned on standard chow consumed 14% more food per day than controls and developed obesity, hyperinsulinemia, and hyperleptinemia. The sim1 heterozygous mice were also significantly longer than controls. Heterozygous animals had modestly increased feeding efficiency, suggesting reduced energy expenditure, but voluntary wheel-running activity did not differ significantly between the two groups. We studied the effect of dietary fat on the feeding behavior of heterozygous sim1 mutant mice. The tempo and severity of weight gain were much greater in animals weaned on a high-fat diet. When acutely challenged with increased dietary fat, sim1 heterozygous mice weaned on the chow diet markedly increased their food consumption and caloric intake, whereas control mice reduced the mass of food they consumed and maintained approximately isocaloric intake. In wild-type adult mice, we detected Sim1 expression in the paraventricular and supraoptic nuclei, as previously reported in neonates, as well as in the amygdala and lateral hypothalamus, all regions implicated in feeding behavior. Our results indicate that Sim1 gene dosage modulates the homeostatic feeding response to increased dietary fat and likely plays a physiological role in the regulation of energy balance. hypothalamus; transcription factor; feeding behavior A MEMBER OF THE basic helix-loop-helix-PAS family of nuclear transcription factors is encoded by the Sim1 gene (6). Mouse Sim1 was originally cloned by virtue of its homology with Drosophila single-minded, a master regulator of central nervous system midline neurogenesis (9, 11). In mammals, Sim1 plays a more specialized role in brain development. The only anatomic defect that has been identified in homozygous sim1-knockout mice, which die shortly after birth, is the complete absence of neurons of the paraventricular nucleus (PVN) and supraoptic nucleus (SON) of the hypothalamus (22). The PVN produces corticotropin-releasing hormone, thyrotropin-releasing hormone, and somatostatin, which regulate ACTH, thyroid-stimulating hormone, and growth hormone secretion by the anterior pituitary. The PVN and SON also synthesize oxytocin and vasopressin, which are released by the posterior pituitary. In addition to its endocrine functions, the PVN has been known for decades to play a key role in energy balance. Lesions of the PVN in adult dogs (15) or rats (19) result in hyperphagic obesity. The PVN integrates orexigenic (e.g., neuropeptide Y and Agouti-related peptide) and anorexigenic (e.g., ␣-melanocyte-stimulating hormone and...

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Section: Discussionmentioning

confidence: 83%

Sim1 gene dosage modulates the homeostatic feeding response to increased dietary fat in mice

Holder

Zhang

Kublaoui

et al. 2004

American Journal of Physiology-Endocrinology and Metabolism

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“…Consistent with this model, several members of the Atonal family are expressed in terminally differentiated cells (Morrow et al, 1999;Lee et al, 2000). In addition, recent studies have suggested a link between one Atonal family protein, NeuroD, and the neuroendocrine/endocrine signaling pathways that control energy balance (Nilaweera et al, 2002;Khoo et al, 2003), and disruptions in NeuroD are associated with the development of certain forms of type 2 diabetes (Malecki et al, 1999). Nevertheless, the importance of Atonal family proteins in the regulation or maintenance of neuropeptide and peptide hormone levels in fully differentiated cells in vivo has not been directly established.…”

Section: Introductionmentioning

confidence: 88%

“…Interestingly, hypothalamic NeuroD mRNA levels are reduced in obese ob/ob and food-deprived mice, suggesting a functional relationship in mature neurons between NeuroD and the neuroendocrine/endocrine signaling pathways that control energy balance (Nilaweera et al, 2002). NeuroD is also required for activity-dependent granule neuron dendritic growth in the intact rat cerebellar cortex (Gaudilliere et al, 2004), and Gal4-NeuroD chimeras can activate insulin promoter elements in response to glucose stimulation of cultured pancreatic beta cells (Khoo et al, 2003).…”

Section: Potential Dual Functionality Of Other Atonal Family Membersmentioning

confidence: 99%

Regulation of Secretory Protein Expression in Mature Cells by DIMM, a Basic Helix–Loop–Helix Neuroendocrine Differentiation Factor

Hewes

Brewster

et al. 2006

J. Neurosci.

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During differentiation, neuroendocrine cells acquire highly amplified capacities to synthesize neuropeptides to overcome dilution of these signals in the general circulation. Once mature, the normal functioning of integrated physiological systems requires that neuroendocrine cells remain plastic to dramatically alter neuropeptide expression for long periods in response to hormonal and electrical cues. The mechanisms underlying the long-term regulation of neuroendocrine systems are poorly understood. Here we show that the Drosophila basic helix-loop-helix protein DIMM, a critical regulator of neuroendocrine cell differentiation, controls secretory capacity in mature neurons. DIMM expression began embryonically but persisted in adults. Through spatial and temporal manipulation of transgene expression in vivo, we defined two phases of prosecretory DIMM activity. During an embryonic critical window, DIMM controlled the differentiation of amplified expression of the neuropeptide leucokinin. At the onset of metamorphosis, levels of DIMM decreased in the insulin-producing cells (IPCs) in parallel with a marked reduction in levels of Drosophila insulin-like peptide 2 and a key neuropeptide biosynthetic enzyme peptidylglycine ␣-monooxygenase (PHM). Overexpression of DIMM in the IPCs prevented the decrease in PHM levels at this stage. In addition, transient overexpression of DIMM in adults produced a dramatic increase in PHM levels in numerous neurons located throughout the brain. These findings provide insights into the mechanisms controlling the maintenance of differentiated cell states, and they suggest an effective means for dynamically adjusting the strength of hormonal signals in diverse homeostatic systems.

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“…cDNAs for mouse Agrp, somatostatin, Crh and Trh were cloned to pBluescript vector to generate digoxigenin-labeled riboprobes. Probes for Pomc, Ghrh, Mash1 and Dlx1 have been described previously (Nilaweera et al, 2002;McNay et al, 2006). The probes for Sf1 and Gad1 were kind gifts from Dr Holly Ingraham at the University of California, San Francisco (CA, USA) and Dr Jane E. Johnson at the University of Texas Southwestern (TX, USA), respectively.…”

Section: Immunohistochemistry and Ishmentioning

confidence: 99%

The LIM-homeobox transcription factor Isl1 plays crucial roles in the development of multiple arcuate nucleus neurons

Lee

2016

Development

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Neurons in the hypothalamic arcuate nucleus relay and translate important cues from the periphery into the central nervous system. However, the gene regulatory program directing their development remains poorly understood. Here, we report that the LIMhomeodomain transcription factor Isl1 is expressed in several subpopulations of developing arcuate neurons and plays crucial roles in their fate specification. Mice with conditional deletion of the Isl1 gene in developing hypothalamus display severe deficits in both feeding and linear growth. Consistent with these results, their arcuate nucleus fails to express key fate markers of Isl1-expressing neurons that regulate feeding and growth. These include the orexigenic neuropeptides AgRP and NPY for specifying AgRP-neurons, the anorexigenic neuropeptide αMSH for POMC-neurons, and two growth-stimulatory peptides, growth hormone-releasing hormone (GHRH) for GHRH-neurons and somatostatin (Sst) for Sst-neurons. Finally, we show that Isl1 directly enhances the expression of AgRP by cooperating with the key orexigenic transcription factors glucocorticoid receptor and brain-specific homeobox factor. Our results identify Isl1 as a crucial transcription factor that plays essential roles in the gene regulatory program directing development of multiple arcuate neuronal subpopulations.

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Hypothalamic bHLH transcription factors are novel candidates in the regulation of energy balance

Cited by 32 publications

References 36 publications

Sim1 gene dosage modulates the homeostatic feeding response to increased dietary fat in mice

Sim1 gene dosage modulates the homeostatic feeding response to increased dietary fat in mice

Regulation of Secretory Protein Expression in Mature Cells by DIMM, a Basic Helix–Loop–Helix Neuroendocrine Differentiation Factor

The LIM-homeobox transcription factor Isl1 plays crucial roles in the development of multiple arcuate nucleus neurons

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