HormonesSteroid Hormone Signaling

Dr. Aga Syed SameerCSIR Lecturer (Demonstrator)Department of Biochemistry,Medical College,Sher-I-Kashmir Institute of Medical Sciences, Bemina, Srinagar, Kashmir, 190010. India.

First MBBS

Lecture No: H 06

Time : 10:00am

Dated: 14/03/2015

Steroid Hormone Signaling

• PEPCK

PEPCK is the key enzyme of gluconeogenesis

Synthesized in liver in response to low levels of blood glucose

Its rate of transcription is controlled via variety of transcription factors being regulated by variety of hormones

PEPCK taps into the non carbohydrate sources of Pyruvate

It bypasses the reaction catalysed by Pyruvate Kinase to supply glucose for the utilization during starving (in between meals) phase of the cell

Steroid Hormone Signaling

Steroid Hormone Signaling

PYRUVATE

PHOSPHOENOL PYRUVATE

OXALO ACETATE

PEPCK

Pyruvate Carboxylase

ATP+ CO2

ADP

GTP

GDP+ CO2

• PEPCK gene

• PEPCK gene has two control sites for the binding of transcription factors

TATA box: Core promoter: Site for assembly of Pre-Initiation complex

Two Other Promoters located at far upstream of gene: CAAT box & GA box: Regulate the processivity of RNA polymerase

• Among various hormones that effect the expression of PEPCK gene and hence its level of mRNA are:

Insulin: Thyroid Hormone: Glucagon: Glucocorticoids

Steroid Hormone Signaling

• Glucocorticoids mediate its signal via “Glucocorticoid Receptor” (GR)

• GR exists in an inactive form in the cytoplasm; complexed with heat shock protein 90 (hsp90)

• On entering the target cell Glucocorticoids bind to GR in cytosolforming H-GR complex and thereby changing its conformation

• This causes the exposure of Nuclear Localization Sequence (NLS) on the Receptor, facilitating the translocation of “H-GR” complex into the nucleus

Steroid Hormone Signaling

• The sites at which Hormone-Transcription factors bind at PEPCK gene are called as “Response Elements” located at 5-UTR of gene

• “H-GR” complex binds to specific DNA sequence called as “Glucocorticoid Response Element” (GRE) located in 5’-UTR of PEPCK gene

5’-AGAACAnnnTGTTCT-3’

• “H-GR” complex binds to promoter sequences of DNA as dimers

• Binding of “H-GR” complex in turn causes increased transcription of PEPCK

Steroid Hormone Signaling

Steroid Hormone Signaling

Steroid Hormone Signaling↓ Blood Glucose

↑ Secretion of glucocorticoids

↑ synthesis of PEPCK mRNA

↑ H-GR Complex

↑ Conversion of Pyruvate to Glucose

Thyroid Hormone Signaling

HormonesLeptin Signaling

Dr. Aga Syed SameerCSIR Lecturer (Demonstrator)

Department of Biochemistry,

Medical College,

Sher-I-Kashmir Institute of Medical Sciences,

Bemina, Srinagar, Kashmir, 190010. India.

Leptin• The white adipose tissue derived hormone

• Leptin in circulation is in proportion to fat stores

• 16kDA protein hormone (167 residues): Chromosome 7

(ENERGY INTAKE AND EXPENDITURE)

• Serves to communicate the “State of Body Energy Repletion” to the central nervous system (CNS) in order to suppress foodintake and permit energy expenditure

• Reproduction, tissue remodeling, regulation of ANS, elements of endocrine system and immune system

• Mutations of “Leptin” or “Leptin Receptor” results in increased food intake in combination with reduced energy expenditure

Leptin Receptor (LR)

• There are multiple forms of LR; all of which are products of single Lepr Gene

• Structural: Six distinct forms: LRa-LRf

• Chain: Three forms: Secreted; Short; Long

• The crucial Receptor for Leptin is LRb

• Many of the effects of Leptin result from actions in the CNS; particularly in Hypothalamus – Site for high LRb mRNA expression

• In Hypothalamus, Leptin acts on neurons that directly or indirectly regulate levels of circulating hormones

Leptin Receptor (LR)

• LRb belongs to cytokine family of proteins.

• Is itself activated by “Dimerisation and Transphosphorylation”

• It stimulates/activates JAK/STAT downstream signaling

• LRb has three functional domains

• Extra Cellular Ligand Binding Domain

• Single TM Domain

• Cytoplasmic Signaling Domain

Leptin Receptor (LR)• LRb is found in several tissues

• Highest expression of LRb is in neurons of several nuclei of the hypothalamus

• Arcuate (ARC)

• Dorsomedial (DMH)

• Ventromedial (VMH)

• Lateral (LHA) hypothalamic area

• Ventral Pre-mammillary nuclei

• The LRb action on ARC nuclei is well characterized:

One population of ARC synthesize Neuropeptide Y (NPY) and Agouti-Related Peptide (AgRP)

Second one synthesize Pro-Opio Melano Cortin (POMC)

Neuro Pepetide Y(NPY)• NPY is orexigenic (Appetite Stimulating) hormone;

• It suppresses the Central LRb mediated growth and reproductive function.

• Leptin via LRb activation leads to positive inhibition of “NYP/AgRP neurons” and suppresses the expression and secretion of NPY and AgRP (Insulin Presence & High Blood Glucose )

• Thus, Leptin in well fed state decreases the levels of circulating “Orexigenic Peptides”

• Consequently; Leptin signals the brain that the body has had enough to eat producing the feeling of satiety

α-Melanocyte Stimulating Hormone

• Leptin is also known to stimulate the synthesis of “POMC” via LRb-POMC neurons

• POMC in turn is processed to produce α-MSH

• α-MSH is known to function as “Anorexic” signal and hence signals brain to have a “decreased” appetite

• This effect is coupled with the effect of absence of NPY

Leptin & Food Intake

Well Fed State

FastingState

Leptin Signaling• LRb is a specialized “Class I cytokine Receptor”

• Mediates signaling by phosphorylation of the critical tyrosine sites after ligand binding; controlled by “Dimerization ” of the receptor

• The LRb-Ligand complex is then activated by “Transphosphorylation” by soluble cytoplasmic protein kinase

• Jak2 plays a role of kinase in phosphorylating the tyrosine moieties of the C Domain of the LRb; Interacting with it via its SH2 domain

• Phosphorylation of Tyr 1138 of LRb; recruits STAT3/5 to LRb/Jak2 complex. On binding they dimerize and then move to their particular gene targets to mediate the signal

Leptin Signaling

Questions?