Food intake:

Obesity is caused by an imbalance between energy intake and expenditure. It is a

result of over eating, increased energy efficiency more energy stored than
burned off, and reduced physical activity. Energy intake involves energy from
protein, CHO and fats. Energy expenditure involves physical activity, diet
thermogenesis and BMR.
Eating behavior is influenced by internal signal metabolic (glc), hormonal
(leptin, insulin) and mechanical (Gastric distension). It is also influenced by food
palatability and psychologically (cortisol stress?).
The hypothalamus controls eating behaviour it receives information from the
adipose tissue on energy reserves via a circulating hormone called LEPTIN.
Leptin is proportional to fat and causes increased energy expenditure (Boxidation lost as heat) and inhibits feeding. The lipostatic theory is that leptin
returns the fat reserves to set point. Everyone has diff set point. Obese
ppl/leptin mutated ppl set point changes and energy not maintained.
The ob gene codes for leptin. Ob/ob mouse = truncated leptin protein. Is obese
(nothing is inhibiting its feeding). Can cause hyperphagia, hypeglycemai ,
hyperinsulinema and hyperplasia of fat cells.
The db gene codes for leptin receptor db/db = dysfunctional leptin receptor.
Mouse cant detect leptin keeps eating becomes obese.
Leptin has a more pronounced effect on stravtion as leptin decrease causes
weight gain.
Leptin injections treat ob/ob mouse but obese people have high leptin already
due to high fat levels and have functional leptin. Obese people have desensitized
leptin receptor signaling due to overexpression of leptin.
(unsure about this )Leptin receptor in hypothalamus: signaling: leptin causes
receptor to dimerise. JAK prteins phosphorylate tyroise residues on cytosolic
and STAT binds and dimerizes too. STAT dimer dissociates from receptor and
enters nucleus as a TF for genes to regulate food intake.
Leptin and its actions:
1. increases energy expenditure:
leptin acts on ARC of hypothalamus which sends sympathetic signals to
adipose tissue. Adr/Noradrenaline acts on B3 adrenergic GPCR on fat cells
increasea adenyl cyclase, cAMP and PKA. PKA acts on lipid droplets and
hydrolyses TAG to FA FA enters mitochondria for TCA cycle and ATP
production. However, PKA also acts on nucleus which activates UCP-1 gene
(uncoupling protein). This enters mitochondria and dissipates proton
gradient meaning ATP isnt formed, instead energy is lost as heat.

2. on food intake:
1st oder signaling high leptin activates anorexigenic peptides (POMC/CART)
and inhibits orexigenic peptides (NPY/AGRP).
POMC broken down to a-MSH acts on melanocrton receptors (MC4R) on OVN
to increase satiety and reduce appetite. CART is coexpressed with POMC.
AGRP antagonizes MC receptors increases appetite.
NPY neuropeptide Y binds to Y1 receptors on POMC neuron and inhibits POMC.
it also acts on LHA (lateral hypothalamic area) to increase appetite.
Therefore high leptin inhibits AGRP/NPY to reduce appetite.
2nd order signaling:
anorexigenic: POMC a-MSH acts on PVN --. Releases of CRH and TRH
CRH cortoctopin releasing hormone acts on adrenal cortex and increases
corticosterone level which inhibits appetite
TRH thyrotrpin releasing hormone acts on anterior pituairtary release
TSH release TH rom thyroid = increase in metabolic rate therefore decreases
weight.
Orexigenic: MCH stimulates feeding and Orexins (released from LHA0
stimulate feeding and keep you awake.
Melanocortin system: a-MSH acts on all receptors ( MC1R on skin and hair, 2 on
adrenal glands, 3 and 4 in hypothalamus involved in appetite). AGRP antagonizes
the receptors. Agouti protein overexpression cal block melanocortin receptors
and induce yellow pigementaion and obesity in mice.
Mutations:
POMC mutation can cause obesity, hyperphagia, red hair.
MC4R mutation hyperphagia, tall stauture and inceased bone mineral density