Nutrition/ Diet 3 - Physiology of Feeding and Satiety Flashcards
Energy Homeostasis
Physiological process whereby energy intake is matched to energy expenditure over time
What 2 factors cause obesity?
What are the 2 major factors that influence obesity
Accessible, tasty calorie dense food
Sedentary lifestyle
Genetics
Environment
What is metabolic syndrome (syndrome X)?
Central obesity plus 2 of:
Blood pressure greater than or equal to 130/85
Triglycerides greater than or equal to 1.7 mol/L
HDL less than 1.03 in males and 1.29 in females (mol/L)
Fasting glucose greater than or equal to 5.6mmol/L
Diabetes mellitus
Possible consequences of metabolic syndrome? (4)
CV disease Dibetes Mellitus Gallstones Cancers More in list
What is the equation for BMI?
Wegith (kg) / square of height (m)
Categories of BMI?
Up to 25 = thin or normal
25-29.9 = overweight
30-39.9 = obese
greater than or equal to 40.0 = morbidly obese
What are some of the consequences of obesity (9)
Stroke (hypertension) Respiratory disease (sleep apnoea) Heart disease (lipids, diabetes, hypertension) Gallbladder disease Osteoarthritis Dementia NAFLD (fatty liver) Diabetes Cancer(Uterus, breast, prostate, colon) Hyperuricemia, gout
Why do we need fat? (3)
Energy storage
Prevention of starvation
Energy buffer during prolonged illness
What is one of the reasons why it is difficult to lose weight?
Increased fat alters brain function in order that the brain views the fat as normal and dieting as a threat to body survival
How does the CNS influence energy balance and body weight (3)?
Behaviour - feeding and physical activity
ANS activity - regulates energy expenditure
Neuroendocrine system - secretion of hormones
(integration of these determines final output - feeding behaviour)
Where does the CNS influences on energy balance get integrated (in order to produce final behaviour)
How do we know this
In the hypothalamus in the brain
Lesioning ventromedial hypothalamus causes obesity
Lesioning lateral hypothalamus causes leaness
What 3 basic concepts underline the control system of energy intake and body weight?
Satiety signalling
Adiposity negative feedback signalling
Food reward
What is satiation?
Sensation of fullness generated during a meal
What is satiety?
Period of time between termination of one meal and the initiation of the next
What is adiposity?
The state of being obese
What does the satiation and satiety processes regulate?
Meal intimation, termination and inter-meal frequency
When satiation signals increase
During meal to limit meal size
What are the satiation signals? (5)
Cholecystokinin (CCK) Peptide YY (PYY3-36) Glucagon-like peptide 1 (GLP-1) Oxyntomodulin (OXM) Obestatin
Cholecystokinin (CKK)?
Secreted from enteroendocrine cells in duodenum and jejunum
Released in proportion to lipids and proteins in meal
Signals via sensory nerves to hindbrain and stimulates hindbrain directly (Nucleus of solitary tract)
Peptide YY (PYY3-36)?
Secreted from endocrine mucosal L-cells of GI tract
Levels increase rapidly post-prandially
Inhibits gastric motility, slows emptying and reduces food intake (Hypo)
Glucagon-like peptide 1 (GLP-1)
Product of pro-glucagon gene
Also released from L cells in response to food ingestion
Inhibits gastric emptying reduces food intake (Hypo, NTS)
Oxyntomodulin (OXM)?
Also from pro-glucagon gene and released from oxyntic cells of small intestine after meal
Acts to suppress appetite - mechanism unclear
Obestatin
Peptide produced from gene that encodes gherkin and released from cells lining stomach/ small intestine
Suggested t reduce food intake - may act to antagonise the actions of gherkin - actions unclear at present
What is a hunger signal?
Ghrelin
What is Gherkin?
Where is it produced and secreted?
How do its levels range?
Octanoylated peptide
Oxyntic cells in stomach
Levels increase before meals and decrease after meals
Levels are raised by fasting and hypoglycaemia
What does peripheral gherkin stimulate?
what does it decrease?
Food intake (hypo) and decreases fat utilisation
What doe gherkin-containing neurons in the hypothalamus do?
Help control fat metabolism, increasing lipogenesis (liver and adipose)
What do feedback loops which control overall energy balance do?
How does this work basically?
they act to maintain constancy of total body energy stores - why weight is stable in lean and obese individuals
Signals are produced in response to body nutritional status
These are sensed in the hypothalamus
These act to modulate food intake and energy expenditure
What central appetite controllers increase food intake when injected into the hypothalamic centres? (3)
Glutamate
Gaba
Opiods
(effects modest/ short lasting)
What central appetite controller acts to suppress food intake?
Monoamines (many drugs developed to suppress food intake but most were withdrawn due to side-effects)
What do adiposity signals do?
2 hormones produced in peripheral tissues which act on the hypothalamic neurones communicating the status of fat stores
What are the 2 adiposity signals?
Where are these each made and released from?
What does these both do?
Leptin - fat cells
Insulin - pancreatic cells
Inform the hypothalamus to alter energy balance and eat less and increase energy burn
What does reduced leptin do?
in mice with a mutation in the leptin gene
Mimic starvation causing unrestrained appetite
What happened in mice with no receptor for leptin therefore meaning no leptin resulting?
They became severely obese (also hyperglycaemic, hyperinsulinemic, insulin resistant)
What are some of the biological roles of leptin (7)?
Pleiotropic hormone Food intake/ energy expenditure/ fat deposition Peripheral glucose homeostasis/ insulin sensitivity Maintenance of immune system Maintenance of reproductive system Angiogenesis Tumourigenesis Bone formation
What does insulin circulate in the body in proportion to?
What has a high levels of insulin receptors?
What does intracerebroventricular insulin do in rodents? (2)
What does neutron specific deletion of the insulin receptor result in?
Proportion to body adiposity
The hypothalamus
Inhibits food intake and decreases body weight
Obesity
What is it in food that is thought to give you pleasure?
Sugar
Fat
(important role in dopamine pathways)
Why is the use of leptin theraputically to treat obese patients limited?
Most obese individuals have severe petit resistance (they have characteristically high leptin levels)
What are the 2 main theories for leptin resistance in diet-induced obesity?
Defective leptin transport into brain
Altered signal transduction following leptin binding to its receptor
Previous drugs for treatment of obesity - Noradrenergics?
Noradrenergics diethylpropion (Tenuate) Mazindol Phentermine (USA not UK) Appetite suppressants acting to inhibit noradrenaline uptake CV side-effects
Serotonergics?
Fenfluramine
Dexfenfluramine
Fluoxetine
Appetite suppressants acting on 5-HT system
Fen. and Dex. no longer used - induced heart disease
Fluoxetine effects on weight modest and weight returned therefore no longer prescribed in the USA/UK
What is Fen-Phen?
Combination of fenluramine and phentermine - very effective but caused potentially fatal pulmonary hypertension and heart valve problems so has therefore been withdrawn
What is Sibutramine?
Selectively inhibits re-uptake of noradrenaline,
5-HT and dopamine.
Decreases food intake and may also increase
thermogenesis.
Effective - though limited (10lbs lost in 1 year)
Major concerns over side-effects (cardiovascular
events and strokes)
Withdrawn (2010), but can be purchased on-line
in weight-loss products
Present drug for treatment of obesity?
How does it work
Side effets?
Orlistat (Senical or Alli)
Inhibits pancreatic lipase decreasing triglyceride absorption
Reduces efficiency of fat absorption (~30%) in small intestine
Side-effects include cramping and severe diarrhoea
Need to take vitamin supplements (fat soluble vitamins)
May not be particularly effective over long-term
(weight loss small (3 kg in 12 months,get ‘rebound’ in weight)
what was the latest anti-obesity drug to fail?
Other uses for this drug?
Why has it been withdrawn?
Rimonabant
Atcs on the endocannabinoid system (system targeted by marijuana active components)
Causes a reduction in appetite
Smoking cessation
Reducing addiction to certain drugs
Improved short-term memory
Causes severe depression, anxiety and increased risk of suicide
Anti-Obesity drugs currently being developed? (3)
Lorcaserin: (Belviq) An agonist at 5-HT2c receptors – designed
to target a different site to fenfluramine (5-HT2b). Inferior to
rimonabant or sibutramine in efficacy (3%). Safety issues raised in
2010 and 2012. FDA approved in June 2012; EMA rejected (2013)
Qsymia: Combination therapy – phentermine + topiramate (an
anticonvulsant). Weight loss in DIO rats better than sibutramine
or rimonabant (5-10%). FDA rejected. But dosage of each drug in
Qsymia reduced – Approved in July 2012; EMA rejected (2013)
Contrave: Combination of bupropion (dopamine re-uptake
inhibitor) + naltrexone (opioid antagonist). Effective in obese
subjects (~5%). FDA declined in 2011. Cardiovascular safety issues.
Further studies and FDA recommended approval in 2014
EMA recently approved (2015) – marketed as Mysimba in EU
New anti-obesity drug currently coming on-line?
Liraglutide (Saxenda)
Licensed for treatment of type 2 diabetes, causes weight loss
Glucagon-like peptide 1 receptor agonist (GLP-1 - a satiety peptide)
Higher doses than used for diabetes produce significant weight loss
FDA approved for obesity treatment, December 2014
EMA recommended for approval January 2015
Mechanism for anti-obesity action unclear – has to be injected
Some concerns remain regarding thyroid and pancreatic cancer
Advantages of gastric by-pass surgery?
Produces substanioncal and sustainable weight loss
Induces a high level of complete resolution of type 2 diabetes
By-pass restricts calorie intake and induces malabsorption of nutrients but resolution of T2D is unclear (involves altered secretion of peptides from the stomach and gut)
What is adaptive thermogenesis
regulated production of heat in response to environmental changes in temperature and diet, resulting in metabolic inefficiency
What do thermogenic adipocytes do?
Increase energy expenditure uncoupling of oxidative metabolism from ATP production
What is the key function of uncoupling protein 1 (UCP 1) (fatty acid activated protein)
Short circuits proton gradient in mitochondria, accelerates fuel oxidation and produces heat