Good morning girls!

I found this article and I thought it was interesting because the sleep disorders are frequent in our society and also because people usually think that sleep is a waste of time and here there are some reasons to sleep correctly ;)

I hope you enjoy it!

Too Little Or Too Much Sleep?

Updated May 2008 - A study just published in the journalSLEEP has attempted to quantify the relationship between duration of sleep and obesity for both children and adults using cross-sectional research from around the world. The study shows that children and adults who are short sleepers have a consistent increased risk of obesity.

Francesco P. Cappuccio, MD, of Warwick Medical School and colleagues identified 12 studies on children and 17 studies on adults that included the following criteria: report of duration of sleep as exposure, body mass index (BMI) as continuous outcome and prevalence of obesity as categorical outcome, number of participants, age and gender.

Dr. Cappuccio said that the study showed a consistent pattern of increased likelihood of being a short sleeper for people who are obese, both children and adults.

"By appraising the world literature, we were able to show some heterogeneity amongst studies in the world. However, there is a striking consistent overall association, in that both obese children and adults had a significantly increased risk of being short sleepers compared to normal weight individuals. 

The size of the association was comparable (1.89-fold increase in children and 1.55-fold increase in adults). This study is important as it confirms that this association is strong and might be of public health relevance. However, it also raises the unanswered question yet of whether this is a cause-effect association. Only prospective longitudinal studies will be able to address the outstanding question," said Dr. Cappuccio.

Sleep and cardiovascular disease

Research from the University of Warwick and University College London published in SLEEP found that both lack of and too much sleep can more than double the risk of death from cardiovascular disease.

Researchers studied the impact of sleep patterns on mortality among 10 308 civil servants included in the "Whitehall II" cohort at two points in their lives (1985-1988 and 1992-1993). Having adjusted for factors such as age, sex, marital status, employment grade, smoking status, physical activity, alcohol consumption, self-rated health, body mass index, blood pressure, cholesterol and other physical illness researchers were able to identify the effect of changes in sleep patterns. They found that those who had cut their sleeping time from the recommended seven hours when first recorded to five hours or less demonstrated by 2004 a 1.7 fold increased risk in mortality from all causes and a two-fold increased risk of death from cardiovascular disease.

Professor Francesco Cappuccio of Warwick Medical School said:

"Fewer hours sleep and greater levels of sleep disturbance have become widespread in industrialized societies. This change, largely the result of sleep curtailment to create more time for leisure and shift-work, has meant that reports of fatigue, tiredness and excessive daytime sleepiness are more common than a few decades ago. Sleep represents the daily process of physiological restitution and recovery, and lack of sleep has far-reaching effects."

The researchers also found that too much sleep was associated with increased mortality with individuals describing an increase in sleep duration to 8 hours or more a night more than twice as likely to die but predominantly from non-cardiovascular causes.

Dr Jane E. Ferrie from University College London Medical School analysed data from 10 308 volunteers between 35 and 55 years of age. Baseline screening (Phase 1) conducted between 1985 and 1988 involved a clinical examination and a self-administered questionnaire. Data collected at Phase 3 (1992-1993) also included a clinical examination (8104 participants) and questionnaire (8642 participants).

Results indicated U-shaped associations between sleep at Phase 1 and Phase 3 and subsequent cardiovascular and non-cardiovascular mortality from all causes. A 110 per cent excess risk was identified in both cases: cardiac mortality associated with a decrease in sleep duration among those sleeping six, seven or eight hours at Phase 1; and non-cardiac mortality with increase in sleep duration among those sleeping seven or eight hours. These associations remained largely the same after adjustment for socio-demographic factors, existing mortality and health-related behaviors.

Francesco Cappuccio explained:

"Short sleep has been shown to be a risk factor for weight gain, hypertension and Type 2 diabetes sometimes leading to mortality but in contrast to the short sleep-mortality association it appears that no potential mechanisms by which long sleep could be associated with increased mortality have yet been investigated. Some candidate causes for this include depression, low socioeconomic status and cancer-related fatigue."

"In terms of prevention, our findings indicate that consistently sleeping around 7 hours per night is optimal for health and a sustained reduction may predispose to ill-health."

Optimum Sleep

The American Academy of Sleep Medicine offers the following advice on how to get an optimal night's sleep:

• Follow a consistent bedtime routine.
• Establish a relaxing setting at bedtime.
• Get a full night's sleep every night.
• Avoid foods or drinks that contain caffeine, as well as any medicine that has a stimulant, prior to bedtime.
• Do not go to bed hungry, but don't eat a big meal before bedtime either.
• Avoid any rigorous exercise within six hours of your bedtime.
• Make your bedroom quiet, dark and a little bit cool.
• Get up at the same time every morning.

Hi girls!!!

 

As I think that the daily habits are very influential in certain diseases. Smoking is a bad habit which is very frequently in our population for that here I leave you an article that I consider  interesting. It´s  a study of Purdue's university :  'Teens' smoking influenced by older siblings, parents' lifelong smoking habits"

 

Do you think that the children of smoking parents smoke? or on the contrary does that your father smokes produces that you don´t do?

 

Should we do preventive medicine with the children of smoking parents?

 

Hope you like it!

Study: Teens' smoking influenced by older siblings, parents' lifelong smoking habits

WEST LAFAYETTE, Ind. - Teens who smoke are significantly influenced by whether older siblings smoke as well as if their parents smoke now or did in the past, according to research from Purdue University.

"It's no surprise that the children of heavy smokers smoked, but what is surprising is that the rate of teens whose parents started smoking later in life or who had quit or reduced their smoking was just as high, if not higher," said Mike Vuolo, an assistant professor of sociology who studies youth behavior and substance use. "The children of later-life smokers were 29 percent more likely to smoke, and that number was higher than children of heavy smokers or those whose parents started smoking as teenagers but had quit or reduced their amount.

"Even though these rates are high, young teens are more likely to smoke if an older sibling does, or if they live with a parent who is a heavy smoker. Based on these findings, antismoking prevention for youth really needs to target the children of parents who smoked at any time in their life, as well as if siblings are smoking."

The findings are published in Pediatrics, and the National Institutes of Health funded the work. The data is based on 214 adults who have been surveyed regularly since 1988 beginning at age 14 in the Youth Development Study. This data covers the adults up to age 38. The 314 children of these adults were ages 11-19. Vuolo, who led the study, also worked with Jeremy Staff, an associate professor of criminology and sociology at Penn State University. The Youth Development Study is run by the University of Minnesota.

"Parents' influence on youth smoking is not new, but the quality of this data has followed the parents for more than 20 years and shows the history of their smoking patterns, specifically length and amount, and how that has affected their children," Vuolo said.

Most previous research also is based on one-time surveys that rely on retrospective feedback from parents.

Because parents' smoking could be tracked for 24 years, the parents could be separated into four groups: non-smokers, heavy smokers, light smokers or those who had quit, and late-onset smokers who didn't start smoking until early adulthood. Eight percent of non-smokers' children had smoked in the past year and 25 percent the children of heavy smokers (at least half a pack a day) reported smoking. The data showed that children of parents who started smoking as teenagers and who had quit or reduced their smoking by age 38 smoked at a rate 23 percent, and the highest percentage of youth smoking, at 29 percent, was by children of parents who started smoking later in life in their 20s.

"The similarities for the three smoking groups were surprising," Vuolo said. "I thought the children of smokers who had reduced their smoking or quit would be significantly lower than the other two groups. We controlled for many variables, such as socioeconomic status and the relationship between the parent and child, but nothing stands out why this is. So we'd like to take a closer look at individual specifics - did parents smoke in front of children or were children exposed to their efforts to quit? More than half of these parents quit smoking, and some of these parents quit smoking when their children were young, so how did that influence their children?"

While the influence of parents' smoking history is attention grabbing, Vuolo said it is important to not overlook the sibling effect.

An older sibling who smokes is 15 times more likely to occur in the heavy smoking households than the non-smoking households, and a younger sibling is six times more likely to smoke if they have an older sibling who smokes.

"In fact, if there was a sibling present in the light smoking or the early-onset smoking environment the effect still holds; it's just that it's much more likely to happen in the heavy smoking households," Vuolo said.

Vuolo plans to continue looking at this topic as well as similar parental influences in alcohol use.

"One aspect to keep in mind is that other research shows that heavy smokers are more likely to have children at younger ages, so they may be overrepresented in this population because they have teenagers at age 38," Vuolo said. "If we did the same analysis 10 years from now, when the non-smokers' children are more likely to be teenagers, what would we see?"

 

 

Psychology of a shopaholic:

 When it’s a real mental disorder

I know that there are articles which go deep and they´re complicated because you don´t understand very well all subtopics that are include in the big one.For these reason I´ve choose this,shopping and psychology is a good couple or mix.

About the topic ,I consider that all of us love going shopping but there is a limit,we can´t obsess with clothes,perfums or make up because our Visa has a limit and I´m sure that we don´t need all things that we have in our  wardrobe.

I hope that results interesting for you and I´m waiting your answers

Thanks.

If you often joke about the wonders of “retail therapy”, you may want to think about it twice. Being a shopaholic might be manifestation of a mental disorder. (Shutterstock)

When people hear the term “shopaholic,” they often think of someone who buys needless items, usually when he or she already has an ample supply. Most of the time the term is used as a way to tease someone who enjoys shopping, but the truth of the matter is compulsive shopping in excess can be a symptom of a real psychological disorder, one professionally referred to as oniomania.

Not everyone who enjoys shopping is a shopaholic; people with oniomania have a compulsive disorder, one that can affect day-to-day activities and personal relationships. For some people, being a shopaholic has broken up families and ended careers.

“‘Shopaholic’ is not an actual medical term but rather a popular expression meant to describe people who compulsively shop, often to their financial and personal detriment,” Lloyd I. Sederer, MD, Medical Director at the NYS Office of Mental Health, tells Saludify. “Like many other compulsive behaviors, it is characterized by its persistence despite a person’s recognizing the problems it causes.”

The facts about being a shopaholic

Oniomania can often occur in conjunction with bipolar disorder and other depressive conditions, and Sederer explains compulsive behaviors in general, provide temporary relief from a variety of difficult feelings, including low mood, low self-regard, intense anxiety, and tensions in personal relationships.

But whatever relief it provides is very transient and typically followed by a resurgence of the feelings the behavior meant to overcome, with the added difficulties of any financial problems the excessive shopping may create.

A common scenario in which someone exhibits symptoms of or tendency to being a shopaholic is when a relationship ends; for example, the woman who goes out and buys an excessive amount of clothing after her boyfriend leaves her. Like Sederer indicates, the purchases are meant to temporarily relieve the pain of relationship loss.

For some experts, a person might become a shopaholic because they become the ‘center of attention’ in a store, where they are tended to continuously.

“Shopping addiction resembles drug, gambling or alcoholic addiction,” psychologist Nadezhda Yugrina told PRAVDA.Ru. “One should look for its reasons in the childhood of every particular individual. As a rule, such people suffered from the shortage of human care and tenderness when children. A person can grow in a normal family and receive good education, but experience a strong need in love. When such people grow up, they can find attention in various stores.”

People often show symptoms of being a shopaholic during stressful life events. (Shutterstock)

Not all compulsive shopping associated with a shopaholic is related to childhood issues or a need to alleviate negative feelings, however. WebMD indicates some individuals may be genetically predisposed to addictive behaviors, which create a “feel good” chemical response in the brain. These addictive behaviors can express in different ways — drugs and alcohol, sex, food and shopping.

“Individuals will get some kind of high from an addictive behavior like shopping,” said toWebMD, Ruth Engs, EdD, a professor of applied health science at Indiana University. “Meaning that endorphins and dopamine, naturally occurring opiate receptor sites in the brain, get switched on, and the person feels good, and if it feels good they are more likely to do it — it’s reinforced.”

Even still, there is another factor which may contribute to oniomania—the presence of another behavioral disorder.

Individuals with Attention Deficit Hyperactivity Disorder (ADHD), for example, are more likely than others to become shopaholics because impulsivity is a part of living with ADHD. This characteristic makes it difficult for these individuals to think of the consequences of over-spending at the time of purchase.

Health Central explains individuals with ADHD can also suffer from anxiety and depression, which bring oniomania back to the category of other addictions and compulsions, which are performed to alleviate stress.

Unfortunately, shopaholics often experience guilt after they get home with their purchases. This can lead to more compulsive shopping, making the process cyclical.

“It is a vicious circle,” said Yugrina. “At first people go to a store and spend a lot of money there but then they suffer from the sense of guilt and go to a store to get rid of this feeling again. If a person wants to put an end to this permanent shopping, they are supposed to approach the issue as a problem and ask for psychological help.”

Treatment for a shopaholic

Being fond of “retail therapy” is not to be taken lightly. We have all experienced the joy of indulging once in a while in something we really need or want. However, if shopping is a constant method of coping, despite financial limitations or distraction from responsibilities, then it’s time to seek help.

Just like with other addictions and compulsions, treatment for a shopaholic often means an intervention followed by support group therapy and one-on-one psychological sessions. In addition to treating the psychological aspect of oniomania, individuals often need to seek financial assistance.

“There are no standard treatments for shopping addiction,” Donald Black, MD, professor of psychiatry at the University of Iowa College of Medicine, told WebMD.

“Medications have been used, generally antidepressants that treat, in some cases, the underlying issue of depression in someone with an addiction, but with mixed results. Therapists also focus on cognitive-behavioral treatment programs, and credit or debt counseling can be very helpful to some people, as well.”

Treatment for a shopaholic can be very costly, not only because of the professional help needed, but because a shopping compulsion does not go away overnight. Throughout the process, individuals with oniomania will likely continue to indulge, running up more debt.

For family and friends, it is important to understand this is an addiction like any other and for the person it might be very difficult to stop at will or from one day to another.

Preventive Double Mastectomy

Hello everybody!

Here you have an article about the double preventive mastectomy. Maybe it seems you familiar because it is the operation that Angelina Jolie did. Here they explain you what type of patients are advised, types of surgery, risks, alternatives to surgery ...

After you read it, would you recommend to your patients? What if the patient is not in the high-risk group but wants to be operated? Would you recommend to a young girl who wants to have children in the future?

Hope you like it!

Surgery to Reduce the Risk of Breast Cancer

          1. What kinds of surgery can reduce the risk of breast cancer?

Two kinds of surgery can be performed to reduce the risk of breast cancer in a woman who has never been diagnosed with breast cancer but is known to be at very high risk of the disease.

A woman can be at very high risk of developing breast cancer if she has a strong family history of breast and/or ovarian cancer, a deleterious (disease-causing) mutation in the BRCA1 gene or the BRCA2 gene, or a high-penetrance mutation in one of several other genes associated with breast cancer risk, such as TP53 or PTEN

The most common risk-reducing surgery is bilateral prophylactic mastectomy (also called bilateral risk-reducing mastectomy). Bilateral prophylactic mastectomy may involve complete removal of both breasts, including the nipples (total mastectomy), or it may involve removal of as much breast tissue as possible while leaving the nipples intact (subcutaneous or nipple-sparing mastectomy). Subcutaneous mastectomies preserve the nipple and allow for more natural-looking breasts if a woman chooses to have breast reconstruction surgery afterward. However, total mastectomy provides the greatest breast cancer risk reduction because more breast tissue is removed in this procedure than in a subcutaneous mastectomy

Even with total mastectomy, not all breast tissue that may be at risk of becoming cancerous in the future can be removed. The chest wall, which is not typically removed during a mastectomy, may contain some breast tissue, and breast tissue can sometimes be found in the armpit, above the collarbone, and as far down as the abdomen—and it is impossible for a surgeon to remove all of this tissue.

The other kind of risk-reducing surgery is bilateral prophylactic salpingo-oophorectomy, which is sometimes called prophylactic oophorectomy. This surgery involves removal of the ovaries and fallopian tubes and may be done alone or along with bilateral prophylactic mastectomy in premenopausal women who are at very high risk of breast cancer. Removing the ovaries in premenopausal women reduces the amount of estrogen that is produced by the body. Because estrogen promotes the growth of some breast cancers, reducing the amount of this hormone in the body by removing the ovaries may slow the growth of those breast cancers.

2. How effective are risk-reducing surgeries?

Bilateral prophylactic mastectomy has been shown to reduce the risk of breast cancer by at least 95 percent in women who have a deleterious (disease-causing) mutation in the BRCA1 gene or the BRCA2 gene and by up to 90 percent in women who have a strong family history of breast cancer

Bilateral prophylactic salpingo-oophorectomy has been shown to reduce the risk of ovarian cancer by approximately 90 percent and the risk of breast cancer by approximately 50 percent in women at very high risk of developing these diseases

3. Which women might consider having surgery to reduce their risk of breast cancer?

Women who inherit a deleterious mutation in the BRCA1 gene or the BRCA2 gene or mutations in certain other genes that greatly increase the risk of developing breast cancer may consider having bilateral prophylactic mastectomy and/or bilateral prophylactic salpingo-oophorectomy to reduce this risk.

Other women who are at very high risk of breast cancer may also consider bilateral prophylactic mastectomy, including:
             o         those with a strong family history of breast cancer
             o         those with lobular carcinoma in situ (LCIS) plus a family history of breast cancer (LCIS is not cancer, but women with LCIS have an increased risk of developing invasive breast cancer in either breast.)
             o         those who have had radiation therapy to the chest (including the breasts) before the age of 30 years—for example, if they were treated with radiation therapy for Hodgkin lymphoma

4. What are the potential harms of risk-reducing surgeries?

As with any other major surgery, bilateral prophylactic mastectomy and bilateral prophylacticsalpingo-oophorectomy have potential complications or harms, such as bleeding or infection. Also, both surgeries are irreversible.

Bilateral prophylactic mastectomy can also affect a woman’s psychological well-being due to a change in body image and the loss of normal breast functions. Although most women who choose to have this surgery are satisfied with their decision, they can still experience anxiety and concerns about body image. The most common psychological side effects include difficulties with body appearance, with feelings of femininity, and with sexual relationships. Women who undergo total mastectomies lose nipple sensation, which may hinder sexual arousal.

Bilateral prophylactic salpingo-oophorectomy causes a sudden drop in estrogen production, which will induce early menopause in a premenopausal woman (this is also called surgical menopause). Surgical menopause can cause an abrupt onset of menopausal symptoms, including hot flashes, insomnia, anxiety, and depression, and some of these symptoms can be severe. The long-term effects of surgical menopause include decreased sex drive, vaginal dryness, and decreased bone density.

5. What can women at very high risk do if they do not want to undergo risk-reducing surgery? 

Some women who are at very high risk of breast cancer (or of contralateral breast cancer) may undergo more frequent breast cancer screening (also called enhanced screening). Enhanced screening may increase the chance of detecting breast cancer at an early stage, when it may have a better chance of being treated successfully.

Women who carry mutations in some genes that increase their risk of breast cancer may be more likely to develop radiation-associated breast cancer than the general population because those genes are involved in the repair of DNA breaks, which can be caused by exposure to radiation. Women who are at high risk of breast cancer should ask their health care provider about the risks of diagnostic tests that involve radiation (mammograms or x-rays).  Ongoing clinical trials are examining various aspects of enhanced screening for women who are at high risk of breast cancer.

Chemoprevention (the use of drugs or other agents to reduce cancer risk or delay its development) may be an option for some women who wish to avoid surgery. Tamoxifen, andraloxifene have both been approved by the FDA to reduce the risk of breast cancer in women at increased risk. Whether these drugs can be used to prevent breast cancer in women at much higher risk, such as women with harmful mutations in BRCA1 or BRCA2 or other breast cancer susceptibility genes, is not yet clear, although tamoxifen may be able to help lower the risk of contralateral breast cancer among BRCA1 and BRCA2 mutation carriers


Source: http://www.cancer.gov/cancertopics/factsheet/Therapy/risk-reducing-surgery

Inma Morcillo

Null Mutation in Hormone-Sensitive Lipase Gene and Risk of Type 2 Diabetes

 I was studying something about the Diabetes and I had some doubts,so I decided to search more information about it.I found this article and for me it´s really interesting knowing how investigations are helping  us and how treatments are helping to million of persons because Diabetes is one of the most common diseases in our world.
I know that it´s long and difficult to follow it,but believe me it´s nice. Enjoy it.

Null Mutation in Hormone-Sensitive Lipase Gene and Risk of Type 2 Diabetes

Both excess and insufficient storage of lipids in white adipose tissue are associated with dyslipidemia, insulin resistance, and an increased risk of type 2 diabetes; thus, maintaining normal white-adipose-tissue function is critical for whole-body insulin sensitivity and energy homeostasis.1Hormone-sensitive lipase (HSL), encoded by LIPE, is an intracellular lipase with many neutral lipid substrates, including triglycerides, diglycerides, monoglycerides, cholesterol esters, and retinyl esters. HSL is ubiquitously expressed and is a key player in lipolysis in adipocytes, steroidogenesis, and spermatogenesis.2

To elucidate the genetic underpinnings of lipid metabolism and white-adipose-tissue function, we sequenced lipolytic-pathway genes in Old Order Amish participants, identified a frameshift mutation in LIPE, and characterized human carriers of this mutation, both systemically and at the level of the adipocyte.

METHODS

We sequenced 12 lipolytic-pathway genes in 24 Old Order Amish study participants whose fasting serum triglyceride levels were at the extremes of the distribution (lower extreme: median, 24 mg per deciliter [range, 14 to 25]; upper extreme: median, 298 mg per deciliter [range, 273 to 608]) and identified a 19-bp deletion in exon 9 of LIPE in one study participant whose triglyceride level was at the upper extreme. We genotyped the deletion in DNA from 2738 study participants enrolled in the Amish Complex Disease Research Program (ACDRP) and carried out tests of association to determine the effect of the deletion on metabolic traits. Biopsy specimens of abdominal subcutaneous white adipose tissue were obtained from 2 study participants who were homozygous for the deletion (DD genotype), 10 who were heterozygous (ID genotype), and 7 who were noncarriers (II genotype) for assessment of adipose histologic characteristics, lipolysis, enzyme activity, cytokine release, and messenger RNA (mRNA) and protein levels. All ACDRP study participants provided written informed consent.

RESULTS

Identification of the LIPE Mutation

We identified a 19-bp frameshift deletion in exon 9 of LIPE (RefSeq NM_005357: c.2300_2318del; p.V767Gfs*102) (Figure 1AFIGURE 1Loss-of-Function Mutation in LIPE with Pedigree Showing Transmission of the Mutation and Metabolic Characteristics.). Of the 2738 participants in the ACDRP study, 140 were heterozygous for the deletion (ID genotype) and 1 was homozygous (DD genotype); 5.1% of Amish persons carry the D allele, as compared with 0.2% of non-Amish persons of European descent. Recruitment of family members of the proband with the DD genotype resulted in the identification of 3 additional DD homozygotes among her 9 siblings (Figure 1B).

Effects of the LIPE Mutation on Metabolic Traits

Demographic and clinical characteristics of the study participants according to LIPE genotype are shown in Table 1TABLE 1Demographic and Clinical Characteristics of the Study Participants, According to LIPE Deletion Genotype.. Carriers of the D allele, as compared with noncarriers, had higher serum triglyceride levels, hepatic fat content, and fasting insulin levels and lower levels of high-density lipoprotein (HDL) cholesterol. In participants without diabetes who completed an oral glucose-tolerance test, the area under the glucose curve and the area under the insulin curve were higher in participants with the ID genotype than in those with the II genotype (Figure S1 in the Supplementary Appendix, available with the full text of this article at NEJM.org). Heterozygotes had a risk of type 2 diabetes that was 1.8 times as high as the risk among noncarriers (P=0.02), despite similar body-mass index, and all four participants with the DD genotype received a diagnosis of type 2 diabetes before 50 years of age. In a subgroup of 52 women matched for age and percentage of body fat, assessment of regional fat by means of dual-energy x-ray absorptiometry showed that the 3 women with the DD genotype had a modest decrease in lower-extremity fat as compared with the 49 women with the II or ID genotype (Table S1 in the Supplementary Appendix).

Further evaluation of the proband and her siblings (Figure 1B) showed that carriers of the D allele (and the homozygotes in particular) had higher triglyceride and insulin levels and lower HDL cholesterol and serum adiponectin levels than did noncarriers, findings that are consistent with population-based data. We observed the expected positive correlation between serum leptin levels and the percentage of body fat in homozygotes for the D allele. Magnetic resonance imaging showed a subtle redistribution of body fat (i.e., decreased lower-extremity fat and increased visceral fat) and — with the exception of the man with the DD genotype, who was lean and very physically active — increased hepatic fat in siblings with the DD genotype as compared with those with the II or ID genotype (Figure 1B, and Figure S2 in the Supplementary Appendix).

Functional Characterization of the LIPE Frameshift Mutation

We confirmed the deletion mutation by reverse-transcriptase–polymerase-chain-reaction amplification of LIPE mRNA from abdominal subcutaneous white adipose tissue (Figure S3 in theSupplementary Appendix). LIPE mRNA levels were lower in tissue samples from participants with the DD genotype than in tissue samples from those with the II genotype; participants with the ID genotype and those with the II genotype had similar LIPE mRNA levels (Figure 2AFIGURE 2Effect of LIPE Mutation on HSL Protein and Function in Adipose Tissue.). Western blot analysis of white-adipose-tissue extracts showed no detectable HSL protein in participants with the DD genotype and approximately a 50% reduction in HSL protein in participants with the ID genotype, as compared with participants who had the II genotype (Figure 2B). In vitro overexpression of nonmutated and mutated LIPE showed no significant difference in mRNA expression (Figure S4A in the Supplementary Appendix) but markedly reduced mutant protein levels (Figure S4B in the Supplementary Appendix), findings that are consistent with the observed lack of in vivo protein expression and that suggest decreased translation or instability of the mutant HSL protein.

Effects of the LIPE Mutation on Adipose Tissue

Dose-dependent reductions in triglyceride lipase activity (Figure 2C) and cholesterol ester hydrolase activity (Figure S5A in the Supplementary Appendix) were observed in white adipose tissue from D allele carriers. The content of diglycerides (Figure S5B in the Supplementary Appendix) and retinyl esters (Figure S5C in the Supplementary Appendix) in white-adipose-tissue lipid extracts was increased in participants with the DD genotype.

Large adipocytes might be expected in participants with a defect in triglyceride hydrolysis, but adipocyte diameter was significantly smaller in samples of abdominal subcutaneous adipose tissue from participants with the DD genotype than in samples from participants with the II genotype (Figure S6 in the Supplementary Appendix). The absence of HSL protein was associated with decreased basal lipolysis; after stimulation with isoproterenol, lipolysis in adipocytes increased by a factor of only 2 in participants with the DD genotype, as compared with an increase by a factor of 5 in participants with the ID or II genotype (Figure 2D). Levels of PNPLA2, encoding adipose triglyceride lipase (ATGL), which catalyzes the first step in the lipolytic pathway,4 were reduced in adipocytes from participants with the DD genotype as compared with adipocytes from participants with the II genotype (Figure S7A in the Supplementary Appendix), as were levels of the ATGL protein (Figure S7B in the Supplementary Appendix).

Sensitivity to the antilipolytic effect of insulin was lower in adipocytes from participants with the DD or ID genotype than in adipocytes from participants with the II genotype; the maximal response to insulin was reduced by approximately 50% in DD homozygotes as compared with II homozygotes (Figure S8A in the Supplementary Appendix). Protein levels of insulin receptor and insulin receptor substrate 1 were also lower in adipocytes from participants with the DD genotype than in adipocytes from participants with the II genotype (Figure S8B and S8C in the Supplementary Appendix). In addition, expression of genes known to be up-regulated with insulin resistance (e.g.,FOXO1 and FABP5) was increased in white adipose tissue from DD homozygotes (Figure S10 in the Supplementary Appendix).

The absence of HSL was associated with histologic abnormalities in white adipose tissue and an increase in macrophage infiltration (a hallmark of inflammation) (Figure S9A in the Supplementary Appendix). Increased mRNA levels of the macrophage chemokine MCP1 (Figure S9B in theSupplementary Appendix) were consistent with the observed increase in macrophage infiltration. Levels of mRNA encoding interleukin-6 in white adipose tissue (Figure S9B in the Supplementary Appendix) and levels of interleukin-6 released from white adipose tissue in culture (Figure S9C in the Supplementary Appendix) were increased in participants with the DD genotype as compared with those with the II genotype.

We observed no significant differences in mRNA levels encoding peroxisome-proliferator–activated receptor γ (PPAR-γ, encoded by PPARG) among the genotype groups; we did, however, observe a comparative decrease in levels of RXRA mRNA, encoding retinoid X receptor α (RXR-α), and in levels of mRNA encoding other key nuclear receptors that regulate lipid and cholesterol metabolism in white adipose tissue from participants with the DD genotype (Figure S10A in the Supplementary Appendix). As expected, down-regulation of critical transcription regulators of terminal differentiation resulted in marked reduction in the expression of downstream target genes involved in the uptake of free fatty acids, the synthesis of free fatty acids and triglycerides, lipolysis, and glucose transport (Figure S10B in the Supplementary Appendix).

DISCUSSION

We identified a loss-of-function mutation affecting HSL that results in haploinsufficiency of the protein in heterozygous study participants and the complete absence of the protein in homozygous participants. Our data indicate that HSL is the predominant, if not exclusive, mediator of the hydrolysis of diglycerides, cholesterol esters, and retinyl esters in human white adipose tissue. The mutation was associated with an increased risk of type 2 diabetes in heterozygotes and with the development of diabetes early in adulthood in homozygotes, with accompanying dyslipidemia, hepatic steatosis, and insulin resistance. In addition to defective lipolysis, the absence of HSL resulted in small, inflamed, insulin-resistant adipocytes — evidence of impaired adipogenesis, impaired adipocyte function, or both.

Phenotypic characterization of carriers of the LIPE deletion revealed that HSL plays a previously unsuspected role in metabolic health. Lower lipolytic rates would be expected to be associated with increased adipose stores5; however, we observed reduced white-adipose-tissue storage. In addition, we observed increased white-adipose-tissue inflammation. Although the sequential contribution of white-adipose-tissue dysfunction and white-adipose-tissue inflammation to metabolic disease has been difficult to establish,6 our data indicate that inflammation is secondary to the primary metabolic defect in white adipose tissue, a phenomenon evident in the genetic disruption of other genes involved in adipocyte lipid-droplet storage (e.g., PLIN1 and CIDEC).7,8

Given our observation of dysmorphic and dysfunctional white adipose tissue in study participants who were homozygous for the LIPE deletion, we hypothesized that HSL deficiency might result in decreased activation of PPAR-γ–regulated pathways in white adipose tissue. We observed no significant difference in PPARG mRNA levels among the genotype groups, but in participants with the DD genotype we observed a marked reduction in the expression of RXRA (RXR-α is an obligate heterodimer partner of PPAR-γ); other critical transcription regulators of terminal differentiation; and genes involved in lipid and glucose metabolic pathways, including the uptake of free fatty acids, the synthesis of free fatty acids and triglycerides, lipolysis, and glucose transport. ATGL is an established PPAR-γ target,9 and its decreased expression in LIPE-null adipocytes probably contributes to the global lipolytic defect but is unlikely to contribute to insulin resistance and type 2 diabetes, because human PNPLA2 mutations that affect ATGL function are not associated with obesity and type 2 diabetes.10 The distinctive gene-expression profile of white adipose tissue in participants with the DD genotype supports our finding that the absence of HSL leads, through altered transcriptional regulation, to impaired adipogenesis, the inability to maintain mature adipocyte functions, or both.

Much of our understanding of the biologic functions of HSL is based on HSL-knockout mouse models. Like the participants with the DD genotype whom we describe here, HSL-knockout mice have normal weight; adipocytes that vary in size, with an accumulation of diglycerides, cholesterol esters, and retinyl esters; increased necrotic cell death; and macrophage infiltration. However, the knockout mice have few or no systemic abnormalities in lipid or glucose homeostasis.11-14 In contrast, haploinsufficiency or absence of HSL in our study participants was characterized by a strong systemic phenotype, with ectopic lipid storage, dyslipidemia, insulin resistance, and diabetes. Impaired lipid storage in human adipocytes probably contributes to ectopic triglyceride accumulation in the liver, which may then contribute to dyslipidemia and systemic insulin resistance. The absence of ectopic lipid storage in HSL-knockout mice suggests an alternative, yet uncharacterized, compensatory mechanism for handling excess lipids. Serum lipid levels also differ markedly between mice and humans: HSL-knockout mice have lower fasting triglyceride and higher HDL cholesterol levels than mice without the deletion, whereas the study participants who were homozygous for the deletion mutation had higher fasting triglyceride levels and lower HDL cholesterol levels than noncarriers. Established interspecies differences in lipoprotein metabolism may contribute to these reversed lipid-level findings. Such phenotypic differences support a key role for HSL in the regulation of lipid and glucose metabolism in humans that is absent or different in mouse models. These differences are consistent with the findings for other lipid-storage regulatory genes, such as PPARG, PLIN1, and CIDEC.7,8,15-18

Despite the relatively subtle metabolic phenotype in HSL-knockout mice, gene-expression profiles in these mice support a regulatory role for HSL in adipogenesis and adipocyte function.11-14,19,20One study showed normalization of serum biochemical values, white-adipose-tissue storage, and gene expression after treatment of HSL-knockout mice with a PPAR-γ agonist.21 Another study showed restoration of retinyl ester hydrolase activity, partial restoration of white-adipose-tissue stores, and normalization of gene expression after treatment with dietary retinoic acid,22 findings that suggest that HSL may be responsible for the release of endogenous ligands for activation of PPAR-γ, RXR-α, or both. Furthermore, ATGL-mediated lipid-droplet hydrolysis of cellular triglycerides was shown to be important in generating essential lipid mediators for PPAR-α and PPAR-δ activation in nonadipose tissues in ATGL-knockout mice.23 It seems that both ATGL and HSL mediate the delivery of specific PPAR and RXR ligands in adipose and nonadipose tissues, despite differences in substrate affinities and specificities.

Although we observed systemic traits such as hepatic steatosis, hypertriglyceridemia, and insulin resistance in study participants who were heterozygous for the LIPE deletion, we did not observe features of marked adipose-tissue dysfunction; these findings suggest that in humans, HSL may have key metabolic functions in nonadipose tissues (e.g., skeletal muscle, the liver, and beta cells) that have not yet been identified. We also note that male HSL-knockout mice are sterile, whereas the male study participant who was homozygous for the LIPE deletion had two children. Further evaluation is needed to determine whether there are differential effects of this mutation on spermatogenesis in male mice and in men.

In summary, we identified a deletion in LIPE, which, when homozygous, results in the complete absence of the HSL protein. Although a defect in an enzyme that is critical for lipolysis would be expected to result in excess lipid storage, we observed the opposite, providing evidence that HSL plays a key role in maintaining adipogenesis and adipocyte function. Furthermore, our results showed marked down-regulation of PPAR-γ–dependent genes that are responsible for adipogenesis and the maintenance of adipocyte function and also showed secondary inflammation, insulin resistance, and impaired glucose and lipid metabolism. These findings are consistent with the hypothesis that HSL deficiency in humans results in decreased production of endogenous ligands for PPAR-γ, RXR-α, or both. Although PPAR-γ agonists are effective agents for the treatment of type 2 diabetes, they can have untoward side effects.24 Our results suggest that activation of HSL with consequent generation of endogenous ligands for PPAR-γ, RXR-α, or both may serve as an alternative means of reversing dyslipidemia and glucose intolerance in the metabolic syndrome and type 2 diabetes. Overall, our findings reveal the physiological significance of HSL in adipocyte function and the regulation of systemic lipid and glucose homeostasis and underscore the severe metabolic consequences of impaired lipolysis.

Supported by grants from the National Institutes of Health (R01DK075017, R01DK74828, U01HL072515, R01DK54261, U01HL84756, U01GM074518, R01HL104193, and R01HL088119), the American Heart Association (11PRE7610008, to Dr. Albert), the University of Maryland Multidisciplinary Clinical Research Career Development Program (NIH K12RR023250, to Dr. Damcott), the Mid-Atlantic Nutrition and Obesity Research Center (NIH P30DK072488), the Baltimore Diabetes Research Center (NIH P60DK079637), the American Diabetes Association, the U.S. Department of Agriculture National Institute of Food and Agriculture (National Research Initiative Competitive Grant 2007-35205-17883), and the Geriatric Research Education and Clinical Center, Baltimore Veterans Affairs (VA) Medical Center, and by a VA Research Career Scientist Award (to Dr. Ryan).

Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.

Drs. Sztalryd and Damcott contributed equally to this article.

This article was published on May 21, 2014, at NEJM.org.

We thank our Amish liaisons and Amish Research Clinic staff, as well as the Amish community for cooperation and support; Cecilia Holm for the hormone-sensitive lipase antibody; Michael Quon and Xiao Jian Sun for the insulin receptor and insulin receptor substrate 1 antibodies; Richa Agarwala and Alejandro Schäffer for assistance in pedigree construction; and Kathy Ryan for data management.

SOURCE INFORMATION

From the Program for Personalized and Genomic Medicine and Department of Medicine, University of Maryland School of Medicine (J.S.A., L.M.Y.-A., R.B.H., T.I.P., U.T.S., S.C., S.S., J.R.O., D.-W.G., J.C.M., A.R.S., C.S., C.M.D.), and the Geriatrics Research and Education Clinical Center (D.-W.G., A.S.R., A.R.S., C.S.), Department of Radiology and Nuclear Medicine (R.J.B.), and the Veterans Affairs (VA) Research Service, Department of Medicine, Division of Gerontology and Geriatric Medicine (A.S.R.), Baltimore VA Medical Center — all in Baltimore; and the Department of Medicine, Columbia University, New York (W.S.B.).

Address reprint requests to Dr. Damcott at the University of Maryland School of Medicine, 660 W. Redwood St., Rm. 592, Baltimore, MD 21201, or at cdamcott@medicine.umaryland.edu.