Starved for fame
Marie Osmond was looking a little plumper when she realized that she needed to slim down for both her health as well as her career. Thus some leptin receptors in the brain are classified as central hypothalamic and some as peripheral non-hypothalamic. Tom and George Virl Osmond, the oldest brothers in the family, were both born deaf. Admittedly, she said it was simply because she had more kids and needed the space to practically live there. Generally, leptin is thought to enter the brain at the choroid plexus , where the intense expression of a form of leptin receptor molecule could act as a transport mechanism.
The Ob Lep gene Ob for obese, Lep for leptin is located on chromosome 7 in humans. A human mutant leptin was first described in ,  and subsequently six additional mutations were described. All of those affected were from Eastern countries; and all had variants of leptin not detected by the standard immunoreactive technique, so leptin levels were low or undetectable. The most recently described eighth mutation reported in January , in a child with Turkish parents, is unique in that it is detected by the standard immunoreactive technique, where leptin levels are elevated; but the leptin does not turn on the leptin receptor, hence the patient has functional leptin deficiency.
A nonsense mutation in the leptin gene that results in a stop codon and lack of leptin production was first observed in mice in In the mouse gene, arginine is encoded by CGA and only requires one nucleotide change to create the stop codon TGA. The corresponding amino acid in humans is encoded by the sequence CGG and would require two nucleotides to be changed to produce a stop codon, which is much less likely to happen.
A recessive frameshift mutation resulting in a reduction of leptin has been observed in two consanguineous children with juvenile obesity. A Human Genome Equivalent HuGE review in looked at studies of the connection between genetic mutations affecting leptin regulation and obesity. They reviewed a common polymorphism in the leptin gene A19G; frequency 0.
They found no association between any of the polymorphisms and obesity. Other rare polymorphisms have been found but their association with obesity are not consistent.
A single case of a homozygous transversion mutation of the gene encoding for leptin was reported in January The transversion of c. The mutant leptin could neither bind to nor activate the leptin receptor in vitro , nor in leptin-deficient mice in vivo. It was found in a two-year-old boy with extreme obesity with recurrent ear and pulmonary infections.
Treatment with metreleptin led to "rapid change in eating behavior, a reduction in daily energy intake, and substantial weight loss". Leptin is produced primarily in the adipocytes of white adipose tissue. Leptin circulates in blood in free form and bound to proteins. Leptin levels vary exponentially, not linearly, with fat mass. In humans, many instances are seen where leptin dissociates from the strict role of communicating nutritional status between body and brain and no longer correlates with body fat levels:.
All known leptin mutations except one are associated with low to undetectable immunoreactive leptin blood levels. The exception is a mutant leptin reported in January which is not functional, but is detected with standard immunoreactive methods.
Predominantly, the "energy expenditure hormone" leptin is made by adipose cells , thus it is labeled fat cell-specific. In the context of its effects , it is important to recognize that the short describing words direct , central , and primary are not used interchangeably.
In regard to the hormone leptin, central vs peripheral refers to the hypothalamic portion of the brain vs non-hypothalamic location of action of leptin; direct vs indirect refers to whether there is no intermediary, or there is an intermediary in the mode of action of leptin; and primary vs secondary is an arbitrary description of a particular function of leptin.
In vertebrates, the nervous system consists of two main parts, the central nervous system CNS and the peripheral nervous system PNS. The primary effect of leptins is in the hypothalamus , a part of the central nervous system. Leptin receptors are expressed not only in the hypothalamus but also in other brain regions, particularly in the hippocampus. Thus some leptin receptors in the brain are classified as central hypothalamic and some as peripheral non-hypothalamic.
Generally, leptin is thought to enter the brain at the choroid plexus , where the intense expression of a form of leptin receptor molecule could act as a transport mechanism. Increased levels of melatonin causes a downregulation of leptin,  however, melatonin also appears to increase leptin levels in the presence of insulin , therefore causing a decrease in appetite during sleeping.
Mice with type 1 diabetes treated with leptin or leptin plus insulin, compared to insulin alone had better metabolic profiles: Leptin acts on receptors in the lateral hypothalamus to inhibit hunger and the medial hypothalamus to stimulate satiety. Thus, a lesion in the lateral hypothalamus causes anorexia due to a lack of hunger signals and a lesion in the medial hypothalamus causes excessive hunger due to a lack of satiety signals.
The absence of leptin or its receptor leads to uncontrolled hunger and resulting obesity. Fasting or following a very-low-calorie diet lowers leptin levels. Leptin binds to neuropeptide Y NPY neurons in the arcuate nucleus in such a way as to decrease the activity of these neurons. Leptin signals to the hypothalamus which produces a feeling of satiety. Moreover, leptin signals may make it easier for people to resist the temptation of foods high in calories.
The NPY neurons are a key element in the regulation of hunger; small doses of NPY injected into the brains of experimental animals stimulates feeding, while selective destruction of the NPY neurons in mice causes them to become anorexic.
Once leptin has bound to the Ob-Rb receptor, it activates the stat3, which is phosphorylated and travels to the nucleus to effect changes in gene expression, one of the main effects being the down-regulation of the expression of endocannabinoids , responsible for increasing hunger. It modulates the immune response to atherosclerosis, of which obesity is a predisposing factor. Exogenous leptin can promote angiogenesis by increasing vascular endothelial growth factor levels.
Hyperleptinemia produced by infusion or adenoviral gene transfer decreases blood pressure in rats. Leptin microinjections into the nucleus of the solitary tract NTS have been shown to elicit sympathoexcitatory responses, and potentiate the cardiovascular responses to activation of the chemoreflex. In fetal lung, leptin is induced in the alveolar interstitial fibroblasts "lipofibroblasts" by the action of PTHrP secreted by formative alveolar epithelium endoderm under moderate stretch.
The leptin from the mesenchyme, in turn, acts back on the epithelium at the leptin receptor carried in the alveolar type II pneumocytes and induces surfactant expression, which is one of the main functions of these type II pneumocytes.
In mice, and to a lesser extent in humans, leptin is required for male and female fertility. Ovulatory cycles in females are linked to energy balance positive or negative depending on whether a female is losing or gaining weight and energy flux how much energy is consumed and expended much more than energy status fat levels.
When energy balance is highly negative meaning the woman is starving or energy flux is very high meaning the woman is exercising at extreme levels, but still consuming enough calories , the ovarian cycle stops and females stop menstruating. Only if a female has an extremely low body fat percentage does energy status affect menstruation. Leptin levels outside an ideal range may have a negative effect on egg quality and outcome during in vitro fertilization.
The placenta produces leptin. Leptin is also expressed in fetal membranes and the uterine tissue. Uterine contractions are inhibited by leptin. Immunoreactive leptin has been found in human breast milk; and leptin from mother's milk has been found in the blood of suckling infant animals. Leptin along with kisspeptin controls the onset of puberty.
Leptin's ability to regulate bone mass was first recognized in Leptin decreases cancellous bone , but increases cortical bone. This "cortical-cancellous dichotomy" may represent a mechanism for enlarging bone size, and thus bone resistance, to cope with increased body weight.
Bone metabolism can be regulated by central sympathetic outflow, since sympathetic pathways innervate bone tissue. Factors that acutely affect leptin levels are also factors that influence other markers of inflammation, e.
While it is well-established that leptin is involved in the regulation of the inflammatory response,    it has been further theorized that leptin's role as an inflammatory marker is to respond specifically to adipose-derived inflammatory cytokines. In terms of both structure and function, leptin resembles IL-6 and is a member of the cytokine superfamily. Similar to what is observed in chronic inflammation, chronically elevated leptin levels are associated with obesity, overeating, and inflammation-related diseases, including hypertension , metabolic syndrome , and cardiovascular disease.
While leptin is associated with body fat mass, however, the size of individual fat cells, and the act of overeating, it is interesting that it is not affected by exercise for comparison, IL-6 is released in response to muscular contractions. Thus, it is speculated that leptin responds specifically to adipose-derived inflammation.
Taken as such, increases in leptin levels in response to caloric intake function as an acute pro-inflammatory response mechanism to prevent excessive cellular stress induced by overeating. When high caloric intake overtaxes the ability of fat cells to grow larger or increase in number in step with caloric intake, the ensuing stress response leads to inflammation at the cellular level and ectopic fat storage, i. The insulin increase in response to the caloric load provokes a dose-dependent rise in leptin, an effect potentiated by high cortisol levels.
This response may then protect against the harmful process of ectopic fat storage, which perhaps explains the connection between chronically elevated leptin levels and ectopic fat storage in obese individuals. Although leptin reduces appetite as a circulating signal, obese individuals generally exhibit a higher circulating concentration of leptin than normal weight individuals due to their higher percentage body fat.
A number of explanations have been proposed to explain this. An important contributor to leptin resistance is changes to leptin receptor signalling, particularly in the arcuate nucleus , however, deficiency of, or major changes to, the leptin receptor itself are not thought to be a major cause.
Other explanations suggested include changes to the way leptin crosses the blood brain barrier BBB or alterations occurring during development. Studies on leptin cerebrospinal fluid CSF levels provide evidence for the reduction in leptin crossing the BBB and reaching obesity-relevant targets, such as the hypothalamus, in obese people.
Since the amount and quality of leptin receptors in the hypothalamus appears to be normal in the majority of obese humans as judged from leptin-mRNA studies ,  it is likely that the leptin resistance in these individuals is due to a post leptin-receptor deficit, similar to the post-insulin receptor defect seen in type 2 diabetes.
When leptin binds with the leptin receptor, it activates a number of pathways. Mice with a mutation in the leptin receptor gene that prevents the activation of STAT3 are obese and exhibit hyperphagia. The PI3K pathway may also be involved in leptin resistance, as has been demonstrated in mice by artificial blocking of PI3K signalling.
The PI3K pathway also is activated by the insulin receptor and is therefore an important area where leptin and insulin act together as part of energy homeostasis. The consumption of a high fructose diet from birth has been associated with a reduction in leptin levels and reduced expression of leptin receptor mRNA in rats.
Long-term consumption of fructose in rats has been shown to increase levels of triglycerides and trigger leptin and insulin resistance,   however, another study found that leptin resistance only developed in the presence of both high fructose and high fat levels in the diet. A third study found that high fructose levels reversed leptin resistance in rats given a high fat diet. The contradictory results mean that it is uncertain whether leptin resistance is caused by high levels of carbohydrates or fats, or if an increase of both, is needed.
Leptin is known to interact with amylin , a hormone involved in gastric emptying and creating a feeling of fullness. When both leptin and amylin were given to obese, leptin-resistant rats, sustained weight loss was seen.
Due to its apparent ability to reverse leptin resistance, amylin has been suggested as possible therapy for obesity. It has been suggested that the main role of leptin is to act as a starvation signal when levels are low, to help maintain fat stores for survival during times of starvation, rather than a satiety signal to prevent overeating.
Leptin levels signal when an animal has enough stored energy to spend it in pursuits besides acquiring food. Dieters who lose weight, particularly those with an overabundance of fat cells, experience a drop in levels of circulating leptin.
This drop causes reversible decreases in thyroid activity, sympathetic tone, and energy expenditure in skeletal muscle, and increases in muscle efficiency and parasympathetic tone.
A decline in levels of circulating leptin also changes brain activity in areas involved in the regulatory, emotional, and cognitive control of appetite that are reversed by administration of leptin. Osteoarthritis and obesity are closely linked. Obesity is one of the most important preventable factors for the development of osteoarthritis. Originally, the relationship between osteoarthritis and obesity was considered to be exclusively biomechanically based, according to which the excess weight caused the joint to become worn down more quickly.
However, today we recognise that there is also a metabolic component which explains why obesity is a risk factor for osteoarthritis, not only for weight-bearing joints for example, the knees , but also for joints that do not bear weight for example, the hands.
Thus, the deregulated production of adipokines and inflammatory mediators, hyperlipidaemia, and the increase of systemic oxidative stress are conditions frequently associated with obesity which can favour joint degeneration. When she was only years-old, Marie Osmond recalls how tough things were for her; particularly when it came to the pressures of staying thin. At the time she was just pounds but stopped eating in order to get down to 97 pounds. Who knew that Donny Osmond was such a talented tech-lover?
The secret video control room at the Flamingo Las Vegas was designed by Donny, along with various audio and computer systems backstage. In one of the most harrowing revelations of the century, Marie Osmond admitted she had a dark secret behind those angelic eyes and cute smile.
In her book, Behind the Smile, Marie talks about the abuse she had to suffer with as a child. In fact, the schedule for the Osmond siblings was so intense it would put most other celebrities to shame. The pair were known to work hour days, having to learn new songs, new dance routines, and dozens of different scripts.
There was never even a hint of exhaustion on either of their faces, however, which is pretty impressive. No one likes their name being spelled wrong, and Donny Osmond was no exception. However, as a forgiving Mormon he also probably let the prank go. As a born performer, Donny Osmond is known for going all out during his performances. Marie Osmond, during an interview, has spoken about how her brother does get carried away sometimes, especially when it comes to dancing on the tables. Ever wondered what a day in the life of Donny Osmond looks like?
Next up, he works out, before doing his show with Marie. He does try and squeeze in some reading on the bus, however. We can imagine it was hard work! Heart disease runs in my family. This minute variety act is seriously intense at times, meaning that Donny gets both his cardio and leg workout from just performing. Back in the s, the pair decided to go their separate ways in order to establish careers as solo artists.
We missed the Osmonds together, so were over the moon when they decided to team back up in their Las Vegas show. The pair found it more difficult than they imagined working together again, with Donny admitting he was no longer the dictator in the twosome.
The pair decided to bring in Barry Leather the director and choreographer to act as the mediator or arbitrator in their working relationship. Donny said when he has time off he would rather go home and see his wife and kids, which makes sense.
He likes to lick salt! The Osmond family have a pretty impressive collection of Gold Records; having received gold certification a whopping four times. Featuring Songs, released in and featuring songs get it from their TV show was the next to receive its gold status. We want another record! Marie was used to living a rather lavish lifestyle from a very young age, having reached the dizzying heights of stardom early.
In between shows, Marie looked forever glam, even with curlers in her hair and an apple in her hand. How does she do it?! The pair then had five children together, all sons; Donald Clark Jr. The entire clan are often seen together having an incredible time, whether it be on vacation or going to church. Donny Osmond enjoyed a fairly successful time on the stages of Broadway, having appeared in no less than three shows. His most recent production saw him take on the role of baddy Gaston, in Beauty and the Beast.
By the looks of this photo, Donny quite enjoyed being the bad guy, even if just for a short while. When Donny appeared on The Kumars at No. Sanjeev Bhaskar, the star of the show, said that his wife had always planned to marry Donny Osmond when she was younger — and even convert to Mormonism.
When Donny appeared on the show, Sanjeev joked to her that she could run off with him if she wanted, as she was so excited. You might not know it, but Donny has lent his voice to plenty of animated TV shows and movies over the years. Turns out his voice sounds just as good animated as it does in real life!
Jimmy Osmond, the youngest of the Osmond family, broke records in the UK; a record he still holds to this day. This made Jimmy the youngest performer to reach the top spot in Britain. Jimmy, however, remains wistful about his childhood.
Tom and George Virl Osmond, the oldest brothers in the family, were both born deaf. This is how the entertainment careers of the Osmonds started, by traveling around trying to raise money for hearing aids. When Marie was named Person of the Year by Diane Sawyer, she admitted that she cried when Jessica first came out to her when she was just Donny was often mocked for being so uncool as he was growing up.
He could have had any girl he wanted or been seriously rock and roll, but felt as though he was too young and that it would go against his devout Mormon principles.
His family of course. He has said that this formula has helped them through a lot of things, despite people thinking he was naive. I grew up fast. Marie Osmond has had her fair share of ups and downs throughout her life, but she seems quite philosophical in the matter. In recent interviews, it seems as though the starlet has found peace.
Living life in the spotlight often meant that the Osmonds grew up with famous friends — the most famous of which was Michael Jackson.
Donny was good friends with MJ and often looks back on their time together fondly. One of his favorite memories was after the American Music Awards when he was just 17 where he asked Michael Jackson if he was hungry. Donny once revealed that whenever they do an interview, Marie specifically asks for the lighting to be changed in a way that suits her.
Jimmy has been quoted as saying that show business is not a fair business, although things are different now. This fortune was amassed from live performances, and the movies and TV shows they were in. The money the family has made through their live entertainment has allowed them to fund their other ventures, feed their families, and live a pretty comfortable life. Marie Osmond has tried not to become a diva throughout her decades of fame, but she did have one request when agreeing to perform at the Flamingo in Las Vegas.
She wanted the larger dressing room. Admittedly, she said it was simply because she had more kids and needed the space to practically live there. Jimmy Osmond has always had a bit of a thing for cars, so when the family were at the height of their career, he would splash out often. He also bought his first house when he was just years-old, presumingly needing somewhere to stash all of the cars he was buying. The photo below shows Jimmy with a DeLorean that is similar to the one he bought in the s.
There were many conspiracy theories as to why Donny Osmond always wore purple socks; from OCD through to them being his lucky charm. She came up with the format of providing each child one color sock, so people could tell who was who.
When Marie turned 16, Lucille Ball offered Marie a trick or two that has stuck with the Osmond daughter forever. This could be why Marie now has to have her lighting in a certain way during interviews and stage performances.
Imagine getting showbiz lessons from Lucille Ball! Luckily, Donny stuck true to his Mormon roots and refused to play any part of the PR game, staying clean his whole life.
Remember the song, Could She Be Mine? In Donny was seeing a girl called Tammy, and his brother was seeing a girl named Debbie. Marie Osmond was looking a little plumper when she realized that she needed to slim down for both her health as well as her career.
And according to the commercials, she allegedly lost dozens of pounds on the nutrisystem diet. However, at around the same time she started on the diet, she also started performing on Dancing with the Stars which required her to work out six hours a day, as well as joined a running club. The oldest of the sons, Donald, is nearly 20 years older than his youngest brother Joshua. The second born son was the first to get married and give Donny a grandchild, while Brandon and Donald Jr.
After the birth of her child Brandon, Marie thought she had a typical case of the baby blues, which occurs after the hormones from the baby are not longer there, creating a hormonal imbalance within the mother. However, the feelings did not go away, and it turned out that she was suffering from postpartum depression. Marie now talks about it extensively, and encourages women to go seek treatment the moment they think that they may have it.