lipids
Saving Fat for Lean Times
Posted on by Lawrence Tabak, D.D.S., Ph.D.
Humans and all multi-celled organisms, or metazoans, have evolved through millennia into a variety of competing shapes, sizes, and survival strategies. But all metazoans still share lots of intriguing cell biology, including the ability to store excess calories as fat. In fact, many researchers now consider fat-storing cells to be “nutrient sinks,” or good places for the body to stash excess sugars and lipids. Not only can these provide energy needed to survive a future famine, this is a good way to sequester extra molecules that could prove toxic to cells and organs.
Here’s something to think about the next time you skip a meal. Fat-storing cells organize their fat reserves spatially, grouping them into specific pools of lipid types, in order to generate needed energy when food is scarce.
That’s the story behind this striking image taken in a larval fruit fly (Drosophila melanogaster). The image captures fat-storing adipocytes in an organ called a fat body, where a larval fruit fly stores extra nutrients. It’s like the fat tissue in mammals. You can see both large and small lipid droplets (magenta) inside polygon-shaped fat cells, or adipocytes, lined by their plasma membranes (green). But notice that the small lipid droplets are more visibly lined by green, as only these are destined to be saved for later and exported when needed into the fly’s bloodstream.
Working in Mike Henne’s lab at the University of Texas Southwestern Medical Center, Dallas, research associate Rupali Ugrankar discovered how this clever fat-management system works in Drosophila [1]. After either feeding flies high-or-extremely low-calorie diets, Ugrankar used a combination of high-resolution fluorescence confocal microscopy and thin-section transmission electron microscopy to provide a three-dimensional view of adipocytes and their lipid droplets inside.
She observed two distinct sizes of lipid droplets and saw that only the small ones clustered at the cell surface membrane. The adipocytes contorted their membrane inward to grab these small droplets and package them into readily exportable energy bundles.
Ugrankar saw that during times of plenty, a protein machine could fill these small membrane-wrapped fat droplets with lots of triacylglycerol, a high-energy, durable form of fat storage. Their ready access at the surface of the adipocyte allows the fly to balance lipid storage locally with energy release into its blood in times of famine.
Ugrankar’s adeptness at the microscope resulted in this beautiful photo, which was earlier featured in the American Society for Cell Biology’s Green Fluorescent Protein Image and Video Contest. But her work and that of many others help to open a vital window into nutrition science and many critical mechanistic questions about the causes of obesity, insulin resistance, hyperglycemia, and even reduced lifespan.
Such basic research will provide the basis for better therapies to correct these nutrition-related health problems. But the value of basic science must not be forgotten—some of the most important leads could come from a tiny insect in its larval state that shares many aspects of mammalian metabolism.
Reference:
[1] Drosophila Snazarus regulates a lipid droplet population at plasma membrane-droplet contacts in adipocytes. Ugrankar R, Bowerman J, Hariri H, Chandra M, et al. Dev Cell. 2019 Sep 9;50(5):557-572.e5.
Links:
The Interactive Fly (Society for Developmental Biology, Rockville, MD)
Henne Lab (University of Texas Southwestern Medical Center, Dallas)
NIH Support: National Institute of General Medical Sciences
Why When You Eat Might Be as Important as What You Eat
Posted on by Dr. Francis Collins
About 1 in 3 American adults have metabolic syndrome, a group of early warning signs for increased risk of type 2 diabetes, heart disease, and stroke. To help avoid such health problems, these folks are often advised to pay close attention to the amount and type of foods they eat. And now it seems there may be something else to watch: how food intake is spaced over a 24-hour period.
In a three-month pilot study, NIH-funded researchers found that when individuals with metabolic syndrome consumed all of their usual daily diet within 10 hours—rather than a more customary span of about 14 hours—their early warning signs improved. Not only was a longer stretch of daily fasting associated with moderate weight loss, in some cases, it was also tied to lower blood pressure, lower blood glucose levels, and other improvements in metabolic syndrome.
The study, published in Cell Metabolism, is the result of a joint effort by Satchidananda Panda, Salk Institute for Biological Sciences, La Jolla, CA, and Pam R. Taub, University of California, San Diego [1]. It was inspired by Panda’s earlier mouse studies involving an emerging dietary intervention, called time-restricted eating (TRE), which attempts to establish a consistent daily cycle of feeding and fasting to create more stable rhythms for the body’s own biological clock [2, 3].
But would observations in mice hold true for humans? To find out, Panda joined forces with Taub, a cardiologist and physician-scientist. The researchers enlisted 19 men and women with metabolic syndrome, defined as having three or more of five specific risk factors: high fasting blood glucose, high blood pressure, high triglyceride levels, low “good” cholesterol, and/or extra abdominal fat. Most participants were obese and taking at least one medication to help manage their metabolic risk factors.
In the study, participants followed one rule: eat anything that you want, just do so over a 10-hour period of your own choosing. So, for the next three months, these folks logged their eating times and tracked their sleep using a special phone app created by the research team. They also wore activity and glucose monitors.
By the pilot study’s end, participants following the 10-hour limitation had lost on average 3 percent of their weight and about 3 percent of their abdominal fat. They also lowered their cholesterol and blood pressure. Although this study did not find 10-hour TRE significantly reduced blood glucose levels in all participants, those with elevated fasting blood glucose did have improvement. In addition, participants reported other lifestyle improvements, including better sleep.
The participants generally saw their metabolic health improve without skipping meals. Most chose to delay breakfast, waiting about two hours after they got up in the morning. They also ate dinner earlier, about three hours before going to bed—and then did no late night snacking.
After the study, more than two-thirds reported that they stuck with the 10-hour eating plan at least part-time for up to a year. Some participants were able to cut back or stop taking cholesterol and/or blood-pressure-lowering medications.
Following up on the findings of this small study, Taub will launch a larger NIH-supported clinical trial involving 100 people with metabolic syndrome. Panda is now exploring in greater detail the underlying biology of the metabolic benefits observed in the mice following TRE.
For people looking to improve their metabolic health, it’s a good idea to consult with a doctor before making significant changes to one’s eating habits. But the initial data from this study indicate that, in addition to exercising and limiting portion size, it might also pay to watch the clock.
References:
[1] Ten-hour time-restricted eating reduces weight, blood pressure, and atherogenic lipids in patients with metabolic syndrome. Wilkinson MJ, Manoogian ENC, Zadourian A, Lo H, Fakhouri S, Shoghi A, Wang X, Fleisher JG, Panda S, Taub PR. Cell Metab. 2019 Jan 7; 31: 1-13. Epub 2019 Dec 5.
[2] Time-restricted feeding without reducing caloric intake prevents metabolic diseases in mice fed a high-fat diet. Hatori M, Vollmers C, Zarrinpar A, DiTacchio L, Bushong EA, Gill S, Leblanc M, Chaix A, Joens M, Fitzpatrick JA, Ellisman MH, Panda S. Cell Metab. 2012 Jun 6;15(6):848-60.
[3] Time-restricted feeding is a preventative and therapeutic intervention against diverse nutritional challenges. Chaix A, Zarrinpar A, Miu P, Panda S. Cell Metab. 2014 Dec 2;20(6):991-1005.
Links:
Metabolic Syndrome (National Heart, Lung, and Blood Institute/NIH)
Obesity (National Institute of Diabetes and Digestive and Kidney Diseases/NIH)
Body Weight Planner (NIDDK/NIH)
Satchidananda Panda (Salk Institute for Biological Sciences, La Jolla, CA)
Taub Research Group (University of California, San Diego)
NIH Support: National Institute of Diabetes and Digestive and Kidney Diseases
Tracking Peptides in Cell Soup
Posted on by Dr. Francis Collins
Credit: William Wimley, Tulane University, New Orleans
If you think this soup looks unappealing for this year’s Thanksgiving feast, you’re right! If you were crazy enough to take a sip, you’d find it to be virtually flavorless—just a salty base (red) with greasy lipid globules (green) floating on top. But what this colorful concoction lacks in taste, it makes up for as a valuable screening tool for peptides, miniature versions of proteins that our bodies use to control many cellular processes.
In this image, William Wimley, an NIH-supported researcher at Tulane University, New Orleans, has stirred up the soup and will soon add some peptides. These peptides aren’t made by our cells, though. They’re synthesized in the lab, allowing Wimley and team to tweak their chemical structures and hopefully create ones with therapeutic potential, particularly as smart-delivery systems to target cells with greater precision and deliver biological cargoes such as drugs [1].
Can Artificial Cells Take Over for Lost Insulin-Secreting Cells?
Posted on by Dr. Francis Collins
Caption: Artificial beta cell, made of a lipid bubble (purple) carrying smaller, insulin-filled vesicles (green). Imaged with cryo-scanning electron microscope (cryo-SEM) and colorized.
Credit: Zhen Gu Lab
People with diabetes have benefited tremendously from advances in monitoring and controlling blood sugar, but they’re still waiting and hoping for a cure. Some of the most exciting possibilities aim to replace the function of the insulin-secreting pancreatic beta cells that is deficient in diabetes. The latest strategy of this kind is called AβCs, short for artificial beta cells.
As you see in the cryo-SEM image above, AβCs are specially designed lipid bubbles, each of which contains hundreds of smaller, ball-like vesicles filled with insulin. The AβCs are engineered to “sense” a rise in blood glucose, triggering biochemical changes in the vesicle and the automatic release of some of its insulin load until blood glucose levels return to normal.
In recent studies of mice with type 1 diabetes, researchers partially supported by NIH found that a single injection of AβCs under the skin could control blood glucose levels for up to five days. With additional optimization and testing, the hope is that people with diabetes may someday be able to receive AβCs through patches that painlessly stick on their skin.
Protein Links Gut Microbes, Biological Clocks, and Weight Gain
Posted on by Dr. Francis Collins
Caption: Lipids (red) inside mouse intestinal cells with and without NFIL3.
Credit: Lora V. Hooper, University of Texas Southwestern Medical Center, Dallas
The American epidemic of obesity is a major public health concern, and keeping off the extra pounds is a concern for many of us. Yet it can also be a real challenge for people who may eat normally but get their days and nights mixed up, including night-shift workers and those who regularly travel overseas. Why is that?
The most obvious reason is the odd hours throw a person’s 24-hour biological clock—and metabolism—out of sync. But an NIH-funded team of researchers has new evidence in mice to suggest the answer could go deeper to include the trillions of microbes that live in our guts—and, more specifically, the way they “talk” to intestinal cells. Their studies suggest that what gut microbes “say” influences the activity of a key clock-driven protein called NFIL3, which can set intestinal cells up to absorb and store more fat from the diet while operating at hours that might run counter to our fixed biological clocks.
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