Cellular bioenergetics as a target for obesity therapy
Obesity = EI > EE
Standard metabolic rate/BMR - rate of energy utilized by an organism in the awake resting state
but not actively digesting food and at thermoneutrality.
Adaptive thermogenesis – heat caused by responses by body to cold temperature and diet.
o Primary sites of action = mitochondria of skeletal muscle and BAT
Losing weight only by calorie restriction:
o Mammals designed to guard against starvation = redundant systems in place to
overcome suppression of one pathway, therefore drug won’t have long term effect.
o Central satiety centers often interconnect with other core regulations in the brain
causing phsycotropic side effects.
o Body has homeostatic mechanism such that weight loss produces an increase in calorific
efficiency = decreases BMR making further weight loss more difficult.
Bioenergetics – studies the flow of chemical bond energy within organisms.
o Takes place in mitochondria where energy from nutrients is released through the
tricarboxylic acid cycle and ETC. Oxygen is consumed, water + CO2 + ATP produced.
ATP distribution throughout the cell:
o Maintenance of Na/K and Ca pumps (30%)
o Protein synthesis (30%)
o Gluconeogenesis, ureagenesis, turnover of CHO and lipid stores (20%)
Interconversion process = inefficient
o Heat lost even in tightly coupled reactions
Entirely uncoupled reactions in humans (thermogenic/energy consuming):
o In all cells, H, Na, K and Ca leak back across membrane channels down electrochemical
o In mitochondria, proton leak ~ 20%
o Muscle tissue:
Inwardly rectifying Ca and Na channels
Cycling of actin-myosin during contraction and relaxation
Triglyceride/fatty-acid cycling (esterification of TG is followed by hydrolysis)
o Regulated proton leak in BAT by UCP1
UCP1 – inner mitochondrial trans membrane protein expressed only in brown adipocytes
UCP1 deficient mice = sensitive to cold temperatures, increased risk to diet induced obesity
Transgenic mice with UCP1 expression in white fat = lean phenotype
UCP2 – expressed at low levels, UCP3 – expressed preferentially in skeletal muscle.
Genetic factors account for 50-90% of variance in weight gain (diff in EE and adaptive
thermogenesis) In mammals, occurs in BAT and skeletal muscle.
o Shivering thermogenesis – caused by cold exposure, function of skeletal muscle
o Non-shivering thermogenesis – function of brown fat
Prolonged cold – even as shivering stops, EE remains elevated.
Newborns do not shiver and maintain body temp by non-shivering brown fat
Heat produced used to maintain body temp
o Diet-induced thermogenesis – triggered by overfeeding, function of brown fat
Luxuskonsumption = a physiological mechanism exists that permits excessive
calorific intake to be dissipated as heat, allowing individuals to eat without
Closely associated with recruitment of BAT by enhanced adregenic activity
Heat produced quickly dissipated to environment to prevent rise in body temp
Pair-fed genetically obese mice – defect in BAT mediated thermogenesis
UCP1 ablated mice = more susceptible to cold temp and have to rely on shivering
UCP1 KO mice at thermoneutrality = lack diet induced thermogenesis and develop obesity
o Diet induced thermogenesis is fully independent on UCP1
Neuronal and hormonal regulation of adaptive thermogenesis
Hypothalamic nuclei in CNS integrate stimuli from 2 separate pathways to reg thermogenesis
o Feed-forward pathway involving cutaneous thermal receptors acting via thermosensory
Cause GABA-ergic interneurons in dorsomedial hypothalamus to disinhibit
thermogenesis-promoting neurons in DMH and driving non-shivering in BAT
o Negative FB pathway involving temp-sensitive neurons in brain
Inhibit SNS outflow to BAT
Adaptive thermogenesis is regulated primarily by SNS.
o Noradrenaline released from SNS regulates brown adipocytes
o Promotes proliferation and differentiation of brown adipocytes
o Directly regulates the thermogenic program of BAT by activating UCP1
o Protects brown adipocytes from TNF-alpha induced apoptosis
Adaptive thermogenesis is also modulated by hormones
o Type 2 iodothyronine deiodinase – regulates amount of active T3 in brown fat
o Leptin, released by white adipocytes – regulates energy balance by effects on