The Somatotrope as a Metabolic Sensor: Deletion of Leptin Receptors Causes Obesity

Childs, Gwen V.; Akhter, Noor; Haney, Anessa; Syed, Muhammad Ali; Odle, Angela K.; Cozart, Michael; Brodrick, Zachary; Gaddy, Dana; Suva, Larry J.; Akel, Nisreen; Crane, Christopher H.; Charlesworth, Amanda; Luque, Raúl M; Chua, Streamson C.; Kineman, Rhonda D.

doi:10.1210/edrv.31.6.9978

Cited by 9 publications

(34 citation statements)

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“…AMPK is activated in hepatocytes, in vivo, by leptin activity, which is directed from the VMH via the sympathetic nervous system (Figure 9). Leptin also similarly stimulates lipolysis in the fat pad [21, 83–85]. An enhanced uptake of leptin into the VMH in Cyp1b1-ko mice is supported by acceleration of the normal fasting-induced decline of serum leptin [21] (Figure 4B).…”

Section: Discussionmentioning

confidence: 99%

Cytochrome P450 1B1: An unexpected modulator of liver fatty acid homeostasis

Larsen

Bushkofsky

Gorman

et al. 2015

Archives of Biochemistry and Biophysics

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Cytochrome P450 1b1 (Cyp1b1) expression is absent in mouse hepatocytes, but present in liver endothelia and activated stellate cells. Increased expression during adipogenesis suggests a role of Cyp1b1 metabolism in fatty acid homeostasis. Wild-type C57BL/6j (WT) and Cyp1b1-null (Cyp1b1-ko) mice were provided low or high fat diets (LFD and HFD, respectively). Cyp1b1-deletion suppressed HFD-induced obesity, improved glucose tolerance and prevented liver steatosis. Suppression of lipid droplets in sinusoidal hepatocytes, concomitant with enhanced glycogen granules, was a consistent feature of Cyp1b1-ko mice. Cyp1b1 deletion altered the in vivo expression of 560 liver genes, including suppression of PPARγ, stearoyl CoA desaturase 1 (Scd1) and many genes stimulated by PPARα, each consistent with this switch in energy storage mechanism. Ligand activation of PPARα in Cyp1b1-ko mice by WY-14643 was, nevertheless, effective. Seventeen gene changes in Cyp1b1-ko mice correspond to mouse transgenic expression that attenuated diet-induced diabetes. The absence of Cyp1b1 in mouse hepatocytes indicates participation in energy homeostasis through extra-hepatocyte signaling. Extensive sexual dimorphism in hepatic gene expression suggests a developmental impact of estrogen metabolism by Cyp1b1. Suppression of Scd1 and increased leptin turnover support enhanced leptin participation from the hypothalamus. Cyp1b1-mediated effects on vascular cells may underlie these changes.

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Section: Discussionmentioning

confidence: 99%

Cytochrome P450 1B1: An unexpected modulator of liver fatty acid homeostasis

Larsen

Bushkofsky

Gorman

et al. 2015

Archives of Biochemistry and Biophysics

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“…An effect on synthesis might affect the data interpretation, specifically, the perceived effectiveness of GH secretagogues as antiobesity agents. Furthermore, the significance of somatotrophs as sensors with the ability to receive metabolic signals and respond to alterations in metabolic pathways has been suggested previously (7). Thus, we here sought to determine the effect of acute excess caloric intake (by high-fat diet [HFD] feeding) on the regulation of hGH synthesis as well as on hGH secretion by the pituitary.…”

Section: Introductionmentioning

confidence: 99%

Energy homeostasis targets chromosomal reconfiguration of the human GH1 locus

Vakili¹,

Jin²,

Cattini³

2014

J. Clin. Invest.

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“…In the pituitary gland, LEP exerts a direct or indirect effect on the secretion and regulation of the adenohypophyseal hormones gowthn hormone (GH), FSH/LH, adrenocorticotrophic hormone (ACTH), thyroid‐stimulating hormone (TSH) and prolactin (PRL) . Numerous studies show that LEP regulates the four main hypothalamic‐pituitary peripheral axes (adrenal, thyroid, gonadal and growth hormone) at different levels …”

Section: Introductionmentioning

confidence: 99%

Delta‐like protein 1 in the pituitary‐adipose axis in the adult male mouse

Bello

Puertas-Avendaño

González-Gómez

et al. 2017

J Neuroendocrinology

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With the aim of studying delta‐like protein 1 (DLK1) with respect to the relationship between adipocyte leptin and adenohypophyseal hormones, we carried out an immunohistochemical study analysing the presence of receptors for these hormones in the pituitary and adipose cells of male wild‐type (WT) mice (Dlk1 +/+) compared to knockout (KO) mice (Dlk1 −/−). The mRNA expression of these molecules was also determined using the reverse transcriptase‐polymerase chain reaction. The results obtained showed that, in WT adipose cells, all of the adenohypophyseal hormone receptors were present, with a higher mRNA expression for growth hormone (GH) receptor and thyroid‐stimulating hormone (TSH) receptor. Of the total cells in the anterior pituitary lobe, 17.09±0.9% were leptin receptor (LEPR) immunoreactive (‐IR), mainly in GH‐IR and prolactin (PRL)‐IR cells (41.5±3.8%; 13.5±1.7%, respectively). In Dlk1 −/− mice, adipocyte cells showed a significant increase in the TSH receptor mRNA expression level. Moreover, the percentage of LEPR‐IR GH cells showed a statistically significant increase compared to controls, from 41.5±3.8% to 53.1±4.0%. By contrast, only 3.0±0.6% of LEP‐IR anterior pituitary cells were detected in Dlk1 KO mice, as opposed to 6.8±1.1% observed in WT mice. The results suggest that relationships exist between adipocytes and pituitary GH, PRL and TSH cells, in addition to an influence with respect to the synthesis and release of pituitary leptin, particularly in PRL cells.

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The Somatotrope as a Metabolic Sensor: Deletion of Leptin Receptors Causes Obesity

Cited by 9 publications

References 0 publications

Cytochrome P450 1B1: An unexpected modulator of liver fatty acid homeostasis

Cytochrome P450 1B1: An unexpected modulator of liver fatty acid homeostasis

Energy homeostasis targets chromosomal reconfiguration of the human GH1 locus

Delta‐like protein 1 in the pituitary‐adipose axis in the adult male mouse

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