Question

Q2. Discuss all three of the following topics;

a. beige (aka brite) fat

b. AMP-activated protein kinase (AMPK)

c. basal metabolic rate (BMI)

Please give a detailed answer. Add supportive equations or flow diagrams if possible.

Thank you.

Answer 1

Adult humans have UCP1-expressing thermogenic adipocytes, known as beige/brite

adipocytes, interspersed in WAT. Chronic exposure to cold or β-adrenergic agonists

increases the recruitment of brown adipocytes, promoting accretion of BAT mass. The same

stimuli also promote the recruitment of brown-like (beige/brite) adipocytes in WAT depots, a

phenomenon known as WAT browning. Both brown and beige cells have thermogenic

features, sharing morphological and molecular characteristics such as multilocularity and

expression of thermogenic genes suggesting their contribution to energy dissipation.

However, beige and brown fat cells exhibit distinct genetic signatures that reflect their

different lineage originsAdult humans have UCP1-expressing thermogenic adipocytes, known as beige/brite

adipocytes, interspersed in WAT. Chronic exposure to cold or β-adrenergic agonists

increases the recruitment of brown adipocytes, promoting accretion of BAT mass. The same

stimuli also promote the recruitment of brown-like (beige/brite) adipocytes in WAT depots, a

phenomenon known as WAT browning. Both brown and beige cells have thermogenic

features, sharing morphological and molecular characteristics such as multilocularity and

expression of thermogenic genes suggesting their contribution to energy dissipation.

However, beige and brown fat cells exhibit distinct genetic signatures that reflect their

different lineage origins. In humans, WAT browning is observed in patients suffering from pheochromocytoma

(catecholamine-secreting tumour), severe burns as well as in cancer cachexia.

Because browning of the human adipose organ may represent a safe strategy to combat

obesity related disorders, it is important to investigate the mechanisms by which human WAT

accumulates brown-like cells. In pheo-patients, the excessive amount of catecholamines

released by the tumour creates an adrenergic hyper-stimulated environment that induces the

browning of the omental WAT]. In a similar way, the accumulation of beige adipocytes

in the subcutaneous adipose tissue (SAT) of burn victims is likely to be related to chronically

elevated circulating levels of noradrenaline (norepinephrine, NE) in the blood as part of a

severe adrenergic stress response.

2) AMP-activated protein kinase (AMPK) is a central regulator of energy homeostasis, which coordinates metabolic pathways and thus balances nutrient supply with energy demand. Because of the favorable physiological outcomes of AMPK activation on metabolism, AMPK has been considered to be an important therapeutic target for controlling human diseases including metabolic syndrome and cancer. Thus, activators of AMPK may have potential as novel therapeutics for these diseases. In this review, we provide a comprehensive summary of both indirect and direct AMPK activators and their modes of action in relation to the structure of AMPK.

Under conditions of low energy, AMPK phosphorylates specific enzymes and growth control nodes to increase ATP generation and decrease ATP consumption. In the past decade, the discovery of numerous new AMPK substrates has led to a more complete understanding of the minimal number of steps required to reprogramme cellular metabolism from anabolism to catabolism. This energy switch controls cell growth and several other cellular processes, including lipid and glucose metabolism and autophagy. Recent studies have revealed that one ancestral function of AMPK is to promote mitochondrial health, and multiple newly discovered targets of AMPK are involved in various aspects of mitochondrial homeostasis, including mitophagy.

It plays an important role in:

1) Exercise: Many biochemical adaptations of skeletal muscle that take place during a single bout of exercise or an extended duration of training, such as increased mitochondrial biogenesis and capacity, increased muscle glycogen,and an increase in enzymes which specialize in glucose uptake in cells such as GLUT4 and hexokinase II are thought to be mediated in part by AMPK when it is activated. Additionally, recent discoveries can conceivably suggest a direct AMPK role in increasing blood supply to exercised/trained muscle cells by stimulating and stabilizing both vasculogenesis and angiogenesis

2) Maximum Life Span: The C. elegans homologue of AMPK, aak-2, has been shown by Michael Ristow and colleagues to be required for extension of life span in states of glucose restriction mediating a process named mitohormesis.

3) Lipid Metabolism: One of the effects of exercise is an increase in fatty acid metabolism, which provides more energy for the cell. One of the key pathways in AMPK's regulation of fatty acid oxidation is the phosphorylation and inactivation of acetyl-CoA carboxylase. Acetyl-CoA carboxylase (ACC) converts acetyl-CoA to malonyl-CoA, an inhibitor of carnitine palmitoyltransferase 1 (CPT-1). CPT-1 transports fatty acids into the mitochondria for oxidation. Inactivation of ACC, therefore, results in increased fatty acid transport and subsequent oxidation. It is also thought that the decrease in malonyl-CoA occurs as a result of malonyl-CoA decarboxylase (MCD), which may be regulated by AMPK.

4) Thyroid Hormone: AMPK and thyroid hormone regulate some similar processes. Knowing these similarities, Winder and Hardie et al. designed an experiment to see if AMPK was influenced by thyroid hormone. They found that all of the subunits of AMPK were increased in skeletal muscle, especially in the soleus and red quadriceps, with thyroid hormone treatment. There was also an increase in phospho-ACC, a marker of AMPK activity.

3) Basal Metabolic Rate

The basal metabolic rate (BMR) has a long history in the evaluation of thyroid function. It measures oxygen consumption under basal conditions of overnight fast and rest from mental and physical exertion. Because standard equipment for the measurement of BMR might not be readily available, the BMR can be estimated from the oxygen consumed over a timed interval by analysis of samples of expired air. The test indirectly measures metabolic energy expenditure or heat production.

Results are expressed as the percentage of deviation from normal after appropriate corrections have been made for age, gender, and body surface area. Low values are suggestive of hypothyroidism, and high values reflect thyrotoxicosis. Normal BMR ranges from negative 15% to positive 5%, most hyperthyroid patients having a BMR of positive 20% or better and hypothyroid patients commonly having a BMR of negative 20% or lower. Different clinical states are known to alter BMR. Fever, pregnancy, pheochromocytoma, adrenergic agonist drugs, cancer, congestive heart failure, acromegaly, polycythemia, and Paget’s disease of the bone are known to increase BMR. Obesity, starvation or anorexia, hypogonadism, adrenal insufficiency, Cushing’s syndrome, immobilization, and sedative drugs are known to decrease BMR.