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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