The Impact of Obesity on Somatotrope Function

NIH Pandemic-Era Grants

Pandemic Era Grants

2024

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Principal Investigator: GWEN V CHILDS
Organization: UNIV OF ARKANSAS FOR MED SCIS
Fiscal Year: 2024
Award: $549,786
Funding agency: National Institute of Diabetes and Digestive and Kidney Diseases

SUMMARY
The prevalence of extreme obesity in adults is increasing precipitously and today more than one-third (39.8%)
of adults are obese. Furthermore, the obese condition is characterized by responses and hormone levels that
encourage the accumulation of more fat. Obese individuals are resistant to the appetite suppressing actions of
leptin and to glucose regulation by leptin and they secrete reduced levels of the lipolytic hormone, growth
hormone (GH) from anterior pituitary (AP) somatotropes. There are significant gaps in knowledge about
mechanisms behind the suppression in GH secretion. In light of the importance of somatotropes as metabolic
sensors and the need for their production of GH, there is a critical need to improve our understanding of
somatotrope responses to the stress of obesity. Like all AP cells, somatotropes display plasticity as they are
remodeled to meet fluctuating hormonal and gender-specific needs of the body. Leptin may directly modulate
somatotrope plasticity, although mechanisms are unknown. Furthermore, the impact of leptin is broad in that
it impacts AP cell maturation. The long-term goal of this laboratory is to elucidate the mechanisms by which
AP cells are regulated in order to respond appropriately to metabolic signals. The specific objectives with the
studies described in this application are to determine the mechanisms by which leptin signals somatotropes,
including the identification of gene expression changes and remodeling that occurs under conditions of diet
induced obesity (DIO). This proposed study will test the central hypothesis that the obese state causes sex-
specific somatotrope dysfunction and compromises responses to environmental stresses. A
secondary hypothesis is that post-transcriptional regulation plays a key role in facilitating AP
remodeling. Aim 1 studies will determine the impact of obesity and recovery to normal weight
on somatotrope remodeling and plasticity. Mice will be subject to diet-induced obesity (DIO) under
thermoneutral conditions and a second cohort of animals will recover normal weight after DIO. Unbiased and
targeted approaches including miRNA sequencing (miRNA-seq), single cell RNA-sequencing (scRNA-seq) and
multiplex protein assays will identify signaling pathway mediators and AP cellular response patterns. Aim 2
studies will ascertain the impact of obesity on somatotrope responses to stress. DIO mice will be
challenged with hypothermia and responses assessed by miRNA-seq and scRNA-seq. Aim 2 will also test the
impact of DIO and environmental stress on mice lacking the translational regulatory protein, Musashi in
somatotropes. This study addresses the biological mechanisms regulating energy balance at the level of the AP
and will clarify how somatotropes are remodeled to respond to the metabolic stress of obesity in a sex-specific
manner. The introduction of targeted and unbiased state-of-the-art technologies presents a unique opportunity
for broader mechanistic insights that are critical to identify targets for therapeutic intervention in the obese
state.

Terms: <21+ years old><Address><Adenohypophyseal Hormones><Adenohypophysis><Adult><Adult Human><Animals><Anterior Pituitary Gland><Anterior Pituitary Hormones><Anterior pituitary><Appetite><Assay><Attenuated><Bioassay><Biological><Biological Assay><Body Weight decreased><Cell Body><Cell Communication and Signaling><Cell Maturation><Cell Signaling><Cells><Desire for food><Differences between sexes><Differs between sexes><Disease><Disorder><Dysfunction><Endocrine Gland Secretion><Exposure to><Expression Signature><Fats><Fatty acid glycerol esters><Functional disorder><GH Cell><Gender><Gene Expression><Gene Expression Profile><Goals><Growth Hormone><Growth Hormone 1><Hormonal><Hormone secretion><Hormones><HuB219><Hyperinsulinemia><Hyperinsulinism><Hypophysis><Hypophysis Cerebri><Hypothermia><Intracellular Communication and Signaling><Knowledge><LEP-R><LEPR Protein><Laboratories><Leptin><Light><Mediating><Mediator><Messenger RNA><Metabolic><Metabolic dysfunction><Metabolic stress><Mice><Mice Mammals><MicroRNA Expression Profiling><Molecular><Morbid Obesity><Murine><Mus><NIH><National Institutes of Health><OB Receptor><OB-R><Ob Gene Product><Ob Protein><Obese Gene Product><Obese Mice><Obese Protein><Obesity><Pars Anterior Pituitary Gland><Pathway interactions><Pattern><Photoradiation><Physiopathology><Pituitary><Pituitary Gland><Pituitary Growth Hormone><Pituitary Nervous System><Play><Post-Transcriptional Control><Post-Transcriptional Regulation><Prevalence><Production><Progenitor Cells><Proteins><Recovery><Regulation><Regulatory Pathway><Regulatory Protein><Research><Resistance><Severe obesity><Sex Differences><Sexual differences><Signal Pathway><Signal Transduction><Signal Transduction Systems><Signaling><Somatotrope Cell><Somatotropin><Stress><Technology><Testing><Therapeutic Hormone><Therapeutic Intervention><United States National Institutes of Health><Weight><Weight Loss><Weight Reduction><adiposity><adult adiposity><adult obesity><adulthood><adults with obesity><attenuate><attenuates><biologic><biological signal transduction><blood glucose regulation><body weight loss><cell type><cohort><corpulence><diet-associated obesity><diet-induced obesity><diet-related obesity><energy balance><environmental stresses><environmental stressor><extreme obesity><gene expression pattern><gene expression signature><genetic regulatory protein><global miRNA profiling><glucose control><glucose homeostasis><glucose regulation><growth hormone cell><growth hormone deficiency><hormonal secretion><improved><insight><insulin regulation><intervention therapy><leptin receptor><leptin-binding protein><mRNA><mRNA Translation><miRNA expression profiling><miRNA sequencing><miRNA-seq><micro RNA expression profiling><microRNA profiling><microRNA sequencing><mouse model><murine model><natural hypothermia><ob/ob mouse><obese individuals><obese people><obese person><obese population><obese subjects><pathophysiology><pathway><pituitary anterior lobe><pituitary gland anterior lobe><post-transcriptional gene regulation><posttranscriptional><posttranscriptional control><posttranscriptional regulation><progenitor cell markers><progenitor cell population><progenitor markers><progenitor population><progenitor stem cell markers><regulatory gene product><resistant><response><scRNA-seq><sensor><sex><sex based differences><sex-dependent differences><sex-related differences><sex-specific differences><single cell RNA-seq><single cell RNAseq><single cell expression profiling><single cell transcriptomic profiling><single-cell RNA sequencing><somatotrope><somatotropic cell><somatotropic hormone><stem><stem and progenitor cell population><stem cell biomarkers><stem cell markers><stem cell population><stem cells><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><transcriptional profile><transcriptional signature><transdifferentiation><weights><wt-loss>