Endocrinology. 2012 Oct;153(10):4705-15.

Ablation of leptin signaling to somatotropes: changes in metabolic factors that cause obesity.

Akhter N, Odle AK, Allensworth-James ML, Haney AC, Syed MM, Cozart MA, Chua S, Kineman R, Childs GV.

Department of Neurobiology and Developmental Sciences, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205, USA.

 

Abstract

Mice with somatotrope-specific deletion of the Janus kinase binding site in leptin receptors are GH deficient as young adults and become obese by 6 months of age. This study focused on the metabolic status of young (3-4.5 month old) preobese mutant mice. These mutants had normal body weights, lean body mass, serum leptin, glucose, and triglycerides. Mutant males and females showed significantly higher respiratory quotients (RQ) and lower energy output, resulting from a higher volume of CO(2) output and lower volume of O(2) consumption. Deletion mutant females were significantly less active than controls; they had higher levels of total serum ghrelin and ate more food. Mutant females also had lower serum insulin and higher glucagon. In contrast, deletion mutant males were not hyperphagic, but they were more active and spent less time sleeping. Adiponectin and resistin, both products of adipocytes, were increased in male and female mutant mice. In addition, mutant males showed an increase in circulating levels of the potent lipogenic hormone, glucose-dependent insulinotropic peptide. Taken together, these results indicate that mutant mice may become obese due to a reduction in lipid oxidation and energy expenditure. This may stem from GH deficiency. Reduced fat oxidation and enhanced insulin sensitivity (in females) are directly related to GH deficiency in mutant mice because GH has been shown by others to increase insulin sensitivity and fat oxidation and reduce carbohydrate oxidation. Gender-dependent alterations in metabolic signals may further exacerbate the future obese phenotype and affect the timing of its onset. Females show a delay in onset of obesity, perhaps because of their low serum insulin, which is lipogenic, whereas young males already have higher levels of the lipogenic hormone, glucose-dependent insulinotropic peptide. These findings signify that leptin signals to somatotropes are vital for the normal metabolic activity needed to optimize body composition.

PMID: 22865370

 

Supplement:

Leptin is a well-known hormone produced by adipocytes and made famous for its appetite inhibitory role, because animals that lacked leptin, or the leptin receptor, became obese from over-eating.   Leptin also appears to be permissive for reproduction and the timing of puberty.  If fat stores drop too low in cases of anorexia, for example, or in athletes (gymnasts or ballet dancers), puberty may be delayed and women may not cycle normally.  Leptin alone can restore fertility if leptin receptors are normal.

Leptin binds to specific receptors (LEPR) on neurons that regulate feeding and lowers appetite and food intake. However, there are leptin receptors all over the body and many workers have wondered about broader functions for leptin at these different sites.  Our laboratory studies cells in the anterior pituitary gland that produce growth hormone (GH), called somatotropes.  These cells have leptin receptors and, in 2008, began a study to determine the significance of leptin to this cell population.  We bred genetically engineered mice to produce progeny in which the leptin receptor gene was deleted only in somatotropes.  We knew that by producing growth hormone, somatotropes were important in growth of long bones and prepubertal development as well as reproduction. Growth hormone also breaks down fat and thus optimizes body composition.  We hypothesized that mutant mice lacking leptin receptors in somatotropes might show slower growth, delayed puberty, or partial infertility.

As it turns out, our hypothesis was only partially correct.  These mutant mice did have lower serum GH and lower numbers of somatotropes storing GH. However, these GH deficient mice did not have delayed puberty.  They did become fat as adults.  Figure 1 shows a chubby 4 month old mutant male mouse weighing 63 gms and Figure 2 shows his mutant son who, at 2.5 months is already 42 gms.  The paper describing the phenotype of this mouse was published in 2011 (1).

Gwen V. Childs-1

Figure 1. Male mouse in which the leptin receptor gene was deleted selectively in somatotropes. These mice develop obesity as early as 3.5-4 months of age.  This mouse was fertile and eventually gained up to 70 gms.

Gwen V. Childs-2

Figure 2.  This is one of the male offspring of the mouse in Figure 1.  At 2.5 months, he is already 42 gms.

 

We then asked the question…why did these mutant mice become fat?  We knew that their levels of leptin receptors in the brain were normal, so it was unlikely that they were overeating.  They never became as obese as mice that lacked leptin or leptin receptors completely.  Therefore, we began studies designed to identify metabolic problems that would contribute to their obesity.  The paper featured at this site describes these studies. (2)

We first tested the metabolic activity of mutants and littermate controls in special chambers (Oxymax, Comprehensive Lab Animal Monitoring, Columbus Instruments), which detected differences in CO2 and Oexchange, as well as activity, sleep and food intake.  We studied these mice before they became obese, because the fat load itself would cause changes in metabolic activity. The paper presents several key factors that contributed to their obesity, as well as sex differences. (2)

We discovered that both mutant males and females preferentially burned carbohydrates rather than fat.  This is monitored by gas exchange and a formula that produces a “Respiratory Quotient” (RQ).  An RQ of 0.7 indicates normal fat burning, however our mice had RQ’s between 0.8 and 0.9, indicating that fat was being stored rather than burned.  Both males and females also had high adiponectin, which is produced by fat cells and associated with adipogenesis.  Another fat cell hormone, resistin, was also high.  Resistin is positively correlated with fat mass and impairs insulin actions on glucose uptake.

The sex differences were interesting.  Females had originally shown a delay in onset of obesity (1) and our studies indicate that this could be due to an enhanced insulin sensitivity (they had low insulin and high glucagon). However, they did exhibit characteristics that would eventually lead to obesity.  They showed reduced activity, coupled with high ghrelin, which is an appetite stimulator.  This led to a higher food intake.  In contrast, males did not eat more food. However, they had problems with sleep, which may have contributed to an enhanced activity level.  They also had high levels of a lipogenic peptide called glucose-dependent insulinotropic peptide or GIP, which increases fatty acid synthesis.  Thus, collectively both males and females exhibited metabolic characteristics that would cause their obesity, however the sex differences  in some of these factors may have caused the difference in timing of the onset of the obesity (1).

 

Gwen V. Childs-3Figure 3. Leptin-GH circuit. 

Left cartoon. Leptin levels may inform somatotropes of fat stores so they can respond by secreting GH to control lipolysis and adiposity.  This highlights the importance of somatotropes as metabolic sensors in the body, sensing levels of fat stores in order to optimize body composition.

Right cartoon. If somatotropes do not have leptin receptors, GH stores and secretion are lowered.  Fat stores thus increase along with adipokines.

 

The importance of this study is two-fold.  First, it shows how important leptin signals are to the direct maintenance of somatotropes and secretion of GH.  GH is critical for the optimization of body composition—building bone and muscle, and breaking down fat.  So, leptin and GH have a partnership. Figure 3 shows that leptin signals levels of fat stores to somatotropes. This in turn helps somatotropes produce and store GH proteins. GH in turn breaks down fat and lowers leptin.  If somatotropes do not receive that leptin signal, they can’t adequately do their job, which is to keep our bodies lean and strong.

Second, the study shows that obesity is not simply due to overeating;  different factors can contribute, including lack of activity, sleep disturbances, and changes in oxidation of fuel. In other words, in males, over-eating did not cause their obesity.  It was caused by lack of fat burning.  Females had abnormal levels of the appetite stimulator ghrelin, so they did overeat, however other factors intervened and they became obese later.

 

References

1.            Childs GV, Akhter N, Haney A, Syed M, Odle A, Cozart M, Brodrick Z, Gaddy D, Suva LJ, Akel N, Crane C, Benes H, Charlesworth A, Luque R, Chua S, Kineman RD 2011 The somatotrope as a metabolic sensor: deletion of leptin receptors causes obesity. Endocrinology 152:69-81

2.            Akhter N, Odle AK, Allensworth-James ML, Haney AC, Syed MM, Cozart MA, Chua S, Kineman R, Childs GV 2012 Ablation of leptin signaling to somatotropes: changes in metabolic factors that cause obesity. Endocrinology 153:4705-4715

 

Acknowledgements:  This study was supported by NIH 1R01HD059056 awarded to Gwen Childs; NIH NCRR P20 RR020146 Project IV awarded to Noor Akhter, GVC mentor; NIH P30 NS047546 (core), NIH R03 HD059066 awarded to Gwen Childs.

 

Contact:Gwen V. Childs-pic4
Gwen Childs, Ph.D., FAAA
Professor and Chair
Dept of Neurobiology and Developmental Sciences
4301 W. Markham, Slot 510
University of Arkansas for Medical Sciences
Little Rock, AR 72205

childsgwenv@uams.edu
http://cytochemistry.net/childs/

 

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