L25 - Metabolism in Obesity and Aging

what is white adipose tissue

tissue where lipid is stored - this is facial, bone marrow, subcutaneous, visceral, gonadal, and some white adipose tissue depots are more highly associated with increased risk for metabolic disease

what is brown adipose tissue

tissue that has high thermogenic potential, so it has the ability to break down fat and glucose as heat instead of storing energy - this maintains body temperature, and consists of cervical, axillary, inguinal, and supraclavicular tissue

what is thermogenesis

dissipation of energy through the production of heat by uncoupling the proton gradient

what is AMPK

adenosine monophosphate-dependent kinase which is a highly conserved fuel sensor and energy gauge that regulates cellular activity based on the balance of ATP, ADP, and AMP

when is AMPK active

when the cell has a low energy charge, and it is activated by an increase in AMP and ADP levels

what are the allosteric activators of AMPK

AMP acts as an allosteric activator, increasing AMPK activity by up to 2,000 fold

what are the inhibitors of AMPK

high levels of ATP

what are the physiological triggers of AMPK

energy starvation, cellular stress, exercise, fasting, or cold exposure

what catabolic pathways are regulated by AMPK

catabolism gets turned on to promote pathways that generate ATP - beta-oxidation (fatty acid breakdown), glucose uptake via GLUT1 and GLUT4, glycolysis, and mitochondrial biogenesis

what anabolic pathways are regulated by AMPK

anabolism is turned off by AMPK to inhibit pathways that consume ATP to promote energy storage - fatty acid synthesis by phosphorylating and inactivating ACC, lipogenesis, gluconeogenesis glucose production in the liver, and glycogen synthesis

what is insulin resistance

a clinical sign of metabolic disease characterized by a cell’s failure to respond properly to insulin

how does insulin resistance reduce cellular response

in this state, cells (adipocytes) show lower glucose uptake and lower lipogenesis

how does insulin resistance impair glucose transport

it is specifically associated with impaired GLUT4 translocation, meaning the transporters that move glucose into the cell do no function correctly

how does insulin-resistance affect the physical cells

insulin-resistant adipocytes are typically larger (hypertrophy) with disorganized cortical actin and unilocular-like lipid droplets

what are the systemic effects of insulin resistance

along with inflammation, it promotes low levels of lipolysis, leading to free fatty acids being stored in other organs, which causes lopotoxicity

how does insulin resistance affect development

it often develops during obesity due to extended overnutrition and a consistently high energy charge in the body

how can metformin work to counteract insulin resistance and improve metabolic health

Metformin can act as the first-line treatment drug for Type II diabetes that works primarily by stimulating AMPK activity by inhibiting Complex I in the mitochondria - this reduces ATP production and increases AMP/ATP ratio which directly activates AMPK

how does metformin affect the liver vs muscles

in the liver, it reduces the release of glucose and inhibits gluconeogenesis while in the muscles, it improves glucose uptake

what are the clinical results of metformin on diabetes

this treatment reduces blood glucose levels, improves insulin sensitivity, and does not cause weight gain

how does AMPK activation work to counteract insulin resistance and metabolic health

by acting as a cellular fuel gauge, and getting activated when the cell’s energy charge is low - when activated, AMPK shifts the cell’s metabolism from storing energy to generating it

how does AMPK activation increase glucose uptake

it stimulates GLUT4 and GLUT1 transporters to bring more glucose into the cell

how does AMPK activation promote fat burning

it inhibits ACC which reduces fatty acid synthesis and increases beta-oxidation, which is fat burning

how does AMPK activation increase browning of adipocytes

browning is where white fat storage cells take on characteristics of brown fat cells (heat production), increasing mitochondrial activity and thermogenesis

what is cellular aging

the time-dependent accumulation of biochemical and molecular “wear and tear” that eventually leads to a loss of cell function

what are the sources of cellular damage in cellular aging

aging begins with the accumulation of damage from endogenous (internal) and exogenous (external locations)

what are the endogenous sources of cellular damage

normal metabolic by-products like ROS, errors in DNA replication, and hydrolysis

what are the exogenous sources of cellular damage

environmental factors like UV light, ionizing radiation, and chemicals like cigarette smoke

what are the molecular consequences of cellular aging

DNA mutations through the oxidation of guanine to 8-oxoguanine (if not repaired, leads to mispairing G:C becoming T:A during replication), mitochondrial dysfunction which leads to further ROS accumulation and a damaging cycle, loss of proteostasis (misfolded protein accumulation), and epigenetic alterations

what is cellular senescence

when damage becomes too extensive for repair mechanisms like base excision repair to handle - consists of cell cycle arrest which stops dividing to prevent passing on the mutations, apoptosis resistance where these “zombie cells” don’t die but persist and accumulate in tissues, and also systemic pathology where the accumulation of these cells leads to functional decline, tissue atrophy, inflammation, and metabolic diseases

what are the therapeutic strategies for cellular aging

stimulating repair by returning metabolism to normal by enhancing the cell’s natural repair pathways, and by senolytics which is a new class of drugs designed to kill senescent cells by turning on their apoptotic pathways, clearing them from the body

what is the 8-oxoguanine repair

OGG1 is a key example of a repair enzyme, and if it is missing (like in knockout mice), the mouse becomes heavier and develops hyperinsulinemia, showing a direct link between failed DNA repair and metabolic disease

what causes the DNA damage of oxidation of guanine to 8-oxoguanine

reactive oxygen species

how does the body repair oxidation of guanine to 8-oxoguanine

via base excision repair to fix the specific lesion by recognizing it with the enzyme 8-Oxoguanine Glycosylase and cleaving it from the sugar-phosphate backbone - this leaves behind an AP site where other enzymes then nick the DNA strand at this location, and DNA polymerase inserts the correct guanine base - DNA ligase then seals the backbone up

why is it important that OGG1 repairs 8-oxoG

if failed to repair, the cell might pair it with adenine instead of cytosine during replication, leading to a permanent mutation (G:C to T:A transversion) that can drive aging or metabolic disease

how can DNA damage/repair contribute to cellular aging

via the accumulation of unrepaired lesions that shift the cell from a functional state to a dysfunctional one - aging is the result if the body’s repair systems being outpaced by biochemical wear and tear, eventually leading to a buildup of “zombie” cells that compromise the whole organism

how does induction of cellular senescence lead to cellular aging

chronic, unrepaired DNA damage acts as a primary trigger for the cellular cell to enter senescence which is a state where the cell permanently stops dividing to prevent damaged DNA from being copied (preventing cancer) but refuses to die

how does tissue dysfunction lead to DNA damage and then cellular aging

as these “senescent” cells accumulate over time, they take up space without performing their normal duties which leads to tissue atrophy and a decline in organ function, which are the physical hallmarks of aging