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neuronal expression of sh2b in regulating energy balance
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Vincent Lowe
994907981
BIO407
Is Obesity a Disease ? Obesity = Energy Balance + imbalance = fat storage - imbalance = fat loss
Risks associated with obesity• Type 2 diabetes• Cardiovascular diseases• Lowered immune function• Non Hodgkin's lymphoma • Hypertension
• Social Costs• Absenteeism• Strain on medical system
But is it a Disease ?
Does Obesity have a Genetic Basis ?
1977 NHLBI twin study 80% correlation of BMI in MZ60% in DZ and 30% from shared environment
Thrifty Gene HypothesisFood sources were inconsistent and varied Evolutionary beneficial to eat more
International journal of Obesity 23 genes responsible for single gene mutations
causing 176 obesity cases244 genes seen in animal models 400+ genes awaiting further reasearch using positional
and qualitative gene analysis
A little background informationA little background information
What does it mean to be Obese ? Body Mass Index
Cheap and efficient Overweight if <25 and >29.9 Obese if <30 Does not account for muscle % and
bone mass
Duel Energy X-ray Analysis Differential imaging to determine
different tissues like fat and bone
Formal Terms Hyperlipidemia , hyperphagia …
Leptin Protein signaling hormone in
fat tissue Stimulates hypothalamus to
increase or decrease appetite
Inhibits Neuropeptide Y (NPY) Agouti related peptide (Agrp)
Stimulates Pre-opiomelanocortin (POMC) A-melanocyte stimulating
hormone (α-MSH)
Errors in communication
Insulin Protein signaling hormone secreted
from pancreas Glucose balance and glycogen
conversion Insulin cycle
Blood glucose rises Insulin secretion Stimulations production of glycogen
synthase Blood glucose drops and homeostasis
is returned
Errors in communication Type 2 diabetes Insulin resistance and hyperglycemia
The Brain & Behaviour
Control of the homostatic levels via Leptin + insulin 2 types of tissues
Neuronal tissue Arcuate nucleus , Lateral Hypothalamus & ventromedial
hypothalamus Hunger / Full loop
Peripheral Tissue Current state of energy reserves and homeostatic levels Adipose tissue , liver , pancreases , stomach ,ect.
Working in conjunction to control motivation and behavior
Results & DiscussionResults & Discussion
Creating the TG and TGKO mice
Obesity & Hyperlipidemia•KO mice had large increase in body weight , almost 1.5X compared to WT•KO also had high FFA & TG levels •KO mice had large fatty livers•Tgko mice had similar weight , TG & FFA levels to WT
Adipocyte Differentiation
•KO mice store more fat tissues•KO adipocytes less differentiated and larger size •KO mice had reduced differentiated preadipocytes•TGKO had less fat and smaller fat cells than WT•3T3-L1 preadipocytes , require Sh2b protein from day 6 onward to create fat cells
Energy Imbalance and Metabolism
•KO mice had increased consumption as well as increased metabolism•KO mice ate more food than WT and TGKO , however net positive balance still present•WT , TG and TGKO mice had similar metabolilic rates•TGKO rescue worked and neuronal SH2b is sufficient to return metabolism and appetite
Insulin and Glucose intolerance•Glucose Tolerance test•Insulin Tolerance test•KO mice had 2x blood glucose level•26X plasma insulin level•Decreased reduction of blood glucose and longer onset to return to homeostasis •TGKO had similar results to wild type
•No peripheral sh2b in pancreas •Reduction of efficiency of insulin system
Leptin Resistance•KO had radically affected Leptin and insulin system •Leptin Tolerance testImmunoblotting and immunoprecitating of hypothalamus for both phosphoralated and active stat3 • tgKO showed almost exactly the same levels of expression as WT•Real time PCR of AGRP ,NPY and POMC •POMC levels were similar in all groupsNPY and AgRP were expressed higher in the KO , and moderately inTGKO•KO group , would be more hungry leading to hyperphagia
Protection from induced HFD obesity
•WT had greater body weight than the TG/TG mice on both Chow and HFD conditions•Leptin systems of TG/TG were more effective than the wild type•TG/TG had thinner and leaner body composition than the wild type •Leptin Resistance & obesity induced from a high fat diet is dose dependent on the neuronal SH2b levels
ConclusionsConclusions
Relevance & Human twin studies Jamshidi Et al.
Sh2b gene is associated with serum leptin and body fat in normal female twins
N=2500 Correlation study with leptin , total fat , waist circumference
and body weight
3 genotype variations Alanine Homozygous – major type Threonie homozygous – minor type Alanine , threonine heterozygous - common type
Relevance & Human twin studies
Places to expand on further research
Neuronal expression is important , but what is the exact role of Pheripheral tissue expression
Isolation of SH2B functions to look at specific roles to enhance purposed mechanism
The role of Leptin in tgKO and the resulting elevation of agrp
Critiques
Sex differences Scope of paper very board
Non representative population Correlation does not equal causation
Questions ? Comments ?Questions ? Comments ?
SH2B, and SH2 adaptor family
SH2B is an adaptor protein One of 3 in the Src homology 2
family 4 similar but different isoforms
SH2B1 is the one of interest in this study
Bind and Phosphoralate protein , cytoplasmic and receptor kinases
Previous experiements yeilded broad obesity findings
A focused view of the relationship of leptin and insulin
Possible pharmaceutical action
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