[MUSIC] Welcome back to my Coursera class Biochemical Principles of Energy Metabolism. This is the last session of week six. So in the previous session, I talked about diabetes. In particular, I emphasized the importance of insulin resistance in the development of Type 2 diabetes. And this the last session, I'm going to focus on the contribution of obesity, okay, and diabetes. So let's begin with the obesity. Obesity is, simply speaking, overweight. And then just definition wise, abnormal or excessive fat accumulation. And it's going to be a huge risk to the health, right? So population, it's very simple. The body mass index, called BMI, can be calculated. The weight in kilograms can be divided by the square of height. Because the BMI, it can have different values, 25, 9 over 30, 29 or whatever. So a person with over 25 BMI values is overweight. So this is more above the 30 range. So why obesity is the problem? Because obesity is the high risk factor to trigger many medical conditions, like Type 2 diabetes, and cardiovascular diseases, and in some cases, cancer, all right? And this obesity, based on the WHO estimation, 65% of the whole world population. Actually they're living in countries where overweight and obesity kills more people than underweight, okay? And roughly 500 million adults in the world are affected by obesity, and along with them, 48 million people are children. So there are many factors to drive obesity. This condition can be driven by genetic factors or hormonal disregulation or metabolic problems and psychological issues and maybe cultural and behavioral factors. And those combination of several factors can drive the unwanted fat accumulation and weight gain. Well, in the regulation of bioenergetics, so weight gain, conceptually very simple. The amount of energy intake far exceeds the amount of calories the body utilizes, okay? So this is positive energy balance, right? Overeating or not making enough physical activity. So the accumulation of extra energy, just storing a form of fat, right? So when we talk about obesity, even though those two hormones like glucagon and insulin are two major hormones related to some biogenetics, homeostasis, but I also want to mention about the leptin hormone, okay? Leptin is, I believe you remembered this hormone. Leptin is satiety hormone made from adipocytes, one of adipokines produced from adipocyte fat cells, okay? So when you are hungry, during the fasting condition, so ghrelin is secreted, right, to drive your orexigenic, food seeking behavior. Leptin is totally opposite, once you become full after meal and this hormone leptin produced and then inhibit hunger, like insulin, and trigger satiety state, right? Again, in your brain hypothalamus regions, in particular arcuate nucleus. This hormone gets upon specific neurons and drive the suppression of appetite, okay? So as you can imagine, many human mutations have been found. And those mutations can cause extreme forms of obesity, in particular childhood obesity with hyperphagia. That means endless eating behaviour. We are looking at leptin knock out mice. Without that leptin knock out condition, mice stop eating, and then very easily become obese. And you're looking at leptin hormones 3D structure. So reduced leptin sensitivity inside your brain, functionally can cause uncontrolled eating, And therefore, physiologically obesity can be easily developed. All right, so let's talk about obesity and insulin resistance. So in the context of Type 2 diabetes, insulin resistance is the key issue medical condition. And obesity is major player to drive this insulin resistance. So even then, I want to clearly mention that this obesity related insulin resistance is not absolutely true. In some populations without severe obesity, even lean people can suffer from insulin resistance, okay? There is no 100% correlation. However, what I want to emphasis here is even then, obesity is definitely a high risk factor for developing insulin resistance and the following Type 2 diabetes. Okay, in that way, I want to emphasize the excess fat as a consequence of insulin resistance. So systemic insulin resistance can be caused by the impaired insulin action in many organs, right? So visceral fat accumulation, that means white adipose tissue, expansion of white adipose tissue, accumulation of fat molecules in obese subject is highly associated, tightly linked to insulin resistance. So how excess fat molecules and excess adipose tissue can lead to this insulin resistance. Therefore, possible explanations elucidated, proposed, and quite established. Number one is white adipose tissue secretes adipokines. One good example is leptin. But in many cases, those other adipokines, actually, they can impair insulin sensitivity, in particular liver and muscle. The other one is ectopic lipid accumulation. So extra lipids, maybe from the excess eating, or the high fat diet, whatever. So lipid molecules are supposed to be stored and processed in adipose tissues. But above the normal range of lipid metabolism, too much lipids can be accumulated. And then accumulation don't occur in the adipose anymore. Rather, those fats can accumulated in liver and skeletal muscle. And those lipids can cause lipotoxicity and those tissues, like liver and muscles, when they are become fatty, and their insulin resistance can be developed. And the third region is adipose tissue. Inside the expanded adipose tissue in obese subjects, there are many immune cells, like macrophages, infiltrated. And they are activated and they secrete proinflammatory cytokines. And proinflammatory cytokines, indeed, one of the key factor to disrupt regular insulin signaling. Thus, the insulin sensitivity can be severely destroyed. Okay, so number four is fatty acid. Excess fat and fatty acids themselves can interfere with the normal insulin signaling pathways in peripheral tissues. So I'm going to explain a little bit further. Okay, conceptually, calorie excess and nutrient excess, and accumulated adipose tissues, and fat excess of triacylglycerols. So fats can be accumulated outside of adipose tissue. Maybe pancreas, maybe skeletal muscles, or liver, or blood vessels. And then, those organs and tissue insulin resistance can be developed. Then later on, it can cause Type 2 diabetes. Okay, so I'm going to show one good example and two good examples for fatty acid dependent insulin signalling this regulation, okay? Conceptually, fatty acid can directly interfere with a normal insulin dependent signalling pathway and cause insulin resistance. Let's talk about saturated fatty acid. So obese situation, excess fat, in particular saturated fatty acid, they're floating around. And then those fatty acid can be transported through the transporter getting into the target cells, cells, and disrupt other various metabolites. I'm not going to show these structures, but diacylgycerol or ceramide and those metabolites can negatively impact upon normal insulin dependency running cascade component. So inhibit IRS1 function, and ceramide inhibit Akt kinase. So you can imagine, in the presence of excess saturated fat, fatty acid, those metabolites can shut down insulin actions. So glucose uptake cannot be done efficiently. It's supposed to be lowered. So it becomes insulin resistant. And the other case is saturated fatty acid can be sensed by toll like receptor. There is membrane receptor. Actually, this receptor is very well known for pathogen recognition. But saturated fatty acid also can be recognized by this membrane receptor. And I'm not going to show all the complicated transaction pathways. Ultimately, the activation of saturated fatty acid dependent, toll like receptor activation induce proinflammatory cytokines, like TNF alpha. And those cytokines can be secreted. And then those cytokines indeed a negative stimuli to suppress insulin signalling pathway. This is like the cell signalling information underlying the saturated fatty acid based impaired insulin signalling transduction. And I believe you can have a conceptual picture about the importance of the obesity in the developed matter of insulin resistance and consequence of Type 2 diabetes. So finally, I'm going to wrap up this week six. So pancreas can sense blood glucose levels. When blood glucose level is high, insulin can be secreted. But when glucose level is low, glucagon can be secreted. So when you talk about diabetes, insulin is the main player. Insulin secreted and then binds to insulin receptor on target cells, peripheral target cells like skeletal muscles. And glucose can be throughout those insulin receptor dependent signalling cascade. Glucose uptake can be triggered. And then glycogen accumulated and then protein synthesis, various synthesis and anabolic pathways are activated in response to insulin. However, without a proper lifestyle and without a regular exercise or genetic vectors, a combination of those elements actually develop insulin resistance. And this insulin resistance can be caused by, in many cases, not 100% but many cases, obesity. And accumulated fats and fatty acid and immune cells infiltrating the abnormally accumulated adipose tissues can interfere regular insulin signalling. And when insulin signaling is not properly working, that target cells become getting into the insulin resistant state. And then this is the primary preceeding event to ultimately drive Type 2 diabetes.
