Leptin at 14 y of age: an ongoing story

In the paper

“When fat mass increases, leptin concentrations increase, which suppresses appetite until weight is lost.”

In the paper

“This RNA encoded a predicted 167-amino acid polypeptide with a signal sequence, which indicated that it was secreted and likely to circulate in plasma.”

In the paper

“The phenotypes of both mutations are strikingly similar, which suggests that the encoded genes function in the same physiologic pathway.”

In the paper

“The leptin receptor was identifiedbiochemically and shown tobe a cytokine family receptor that is expressed broadly (24).”

What the sources say

• Not checked yetcites [24] Tartaglia, 1995, Identification and expression cloning of a leptin receptor, OB-R., Cell source

In the paper

“Leptin concentrations increase with accretion of adipose tissue mass and decrease when adipose mass is lost (22).”

What the sources say

• Not checked yetcites [22] Maffei, 1995, Leptin levels in human and rodent: measurement of plasma leptin andob RNA in obese and weight-reduced subjects., Nat Med source

In the paper

“Leptin circulates in blood and acts on the brain to regulate food intake and energy expenditure.”

In the paper

“brain centers in the hypothalamus receive peripheral signals that reflect an organism's nutritional state as part of a feedback loop or loops that maintain homeostatic control of body weight (14,15).”

What the sources say

• Not checked yetcites [14] Brobeck, 1946, Mechanism of the development of obesity in animals with hypothalamic lesions., Physiol Rev source
• Not checked yetcites [15] Mayer, 1955, Regulation of energy intake and the body weight: the glucostatic theory and the lipostatic hypothesis., Ann NY Acad Sci source

In the paper

“The failure of recombinant leptin to alter food intake or weight in db mice established the specificity of the effect and essentially excluded the possibility that the protein reduced weight as a result of an aversive effect (2).”

What the sources say

• Not checked yetcites [2] Halaas, 1995, Weight-reducing effects of the plasma protein encoded by the obese gene., Science source

In the paper

“All these data suggested that there must be a biological system that regulates food intake and maintains homeostatic control of body weight (12).”

What the sources say

• Not checked yetcites [12] Adolph, 1947, Urges to eat and drink in rats., Am J Physiol source

In the paper

“Results from parabiosis experiments were consistent with this possibility and further suggested that the ob gene encoded a circulating factor that suppressed food intake and body weight and that the db gene encoded its receptor.”

In the paper

“It was subsequently shown that leptin receptor RNA was alternatively spliced and that only one of the splice variants, referred to as ObRb at the time (also known as LepR-l), was mutant in C57Bl/Ks db/db mice (25,26).”

What the sources say

• Not checked yetcites [25] Lee, 1996, Abnormal splicing of the leptin receptor indiabetic mice., Nature source
• Not checked yetcites [26] Chen, 1996, Evidence that the diabetes gene encodes the leptin receptor: identification of a mutation in the leptin receptor gene indb/db mice., Cell source

In the paper

“The ob gene was cloned in 1994, and leptin was identified in 1995 as the product of the ob gene and a hormonal signal that regulates energy balance (1)(2)(3)(4).”

What the sources say

• Not checked yetcites (1)(2)(3)(4)

In the paper

“body weight could be altered, in either direction, by introducing specific lesions in the hypothalamus in which ventromedial hypothalamic lesions caused obesity and lateral hypothalamic lesions caused leanness (13).”

What the sources say

• Not checked yetcites [13] Hetherington, 1942, The spontaneous activity and food intake of rats with hypothalamic lesions., Am J Physiol source

In the paper

“Recessive mutations in the leptin gene are associated with massive obesity in mice and in some humans, which establishes a genetic basis for obesity.”

In the paper

“Injections or infusions of leptin reduce food intake and body weight of wild-type and ob mice but have no effect on db mice (2)(3)(4)23).”

What the sources say

• Not checked yetcites (2)(3)(4)23)

In the paper

“to explain the striking stability of weight in living organisms in a stable environment, organisms would need a means for maintaining a constancy of energy stores (5).”

What the sources say

• Not checked yetcites [5] Bray, 1990, Obesity: historical development of scientific and cultural ideas., Int J Obes

In the paper

“The first law of thermodynamics applies similarly to inanimate and biological systems.”

What the sources say

• Not checked yetcites [5] Bray, 1990, Obesity: historical development of scientific and cultural ideas., Int J Obes

In the paper

“When fat mass decreases, plasma leptin concentrations decrease, which stimulates appetite and suppresses energy expenditure until fat mass is restored.”

In the paper

“In 1994 the ob gene was identified by positional cloning as an '4.5 kb RNA that was expressed exclusively in adipose tissue (1).”

What the sources say

• Not checked yetcites [1] Zhang, 1994, Positional cloning of the mouse obese gene and its human homologue., Nature source

In the paper

“The gene is disrupted in the 2 available alleles of ob; in the original C57/Bl6J ob/ob mutation, a nonsense mutation disrupts protein function, whereas in the second coisogenic ob 2j mutation, a retroviral insertion abrogrates expression of the coding sequence altogether (2,21).”

What the sources say

• Not checked yetcites [2] Halaas, 1995, Weight-reducing effects of the plasma protein encoded by the obese gene., Science source
• Not checked yetcites [21] Moon, 1997, The molecular basis of the obese mutation in ob2J mice., Genomics source

In the paper

“The aforementioned studies using the parabiotic union of mice with lesions of the ventromedial hypothalamus to normal rats further suggested that this receptor was localized in the hypothalamus.”

In the paper

“Leptin is a peptide hormone secreted by adipose tissue and regulates adipose tissue mass and energy balance.”

In the paper

“Leptin circulates in the plasma of all mammals tested, including humans and rodents, as an '16-kD protein with a single disulfide bond that is required for bioactivity (2).”

What the sources say

• Not checked yetcites [2] Halaas, 1995, Weight-reducing effects of the plasma protein encoded by the obese gene., Science source

In the paper

“The leptin receptor signals via the Janus kinase-signal transducers and activators of transcription (JAK-Stat) pathway, which depends in part on phosphorylation of tyrosine residues of specific protein substrates, including Stat3 (45).”

What the sources say

• Not checked yetcites [45] Vaisse, 1996, Leptin activation of Stat3 in the hypothalamus of wild-type and ob/ob mice but not db/db mice., Nat Genet source

In the paper

“Importantly, mice with haploinsufficiency for either of these genes are resistant to obesity, remain lean on a high-fat diet, and retain leptin sensitivity (46,47).”

What the sources say

• Not checked yetcites [46] Bjørbaek, 1998, Identification of SOC-3 as a potential mediator of central leptin resistance., Mol Cell source
• Not checked yetcites [47] Zabolotny, 2008, Protein-tyrosine phosphatase 1B expression is induced by inflammation in vivo., J Biol Chem source

In the paper

“Leptin's efficacy was first shown to be variable in rodents in which there was a spectrum of leptin sensitivity among different strains; animals in leptin-deficient states had extreme leptin sensitivity and animals with leptin receptor mutations were the most resistant (23).”

What the sources say

• Not checked yetcites [23] Halaas, 1997, Physiological response to long-term peripheral and central leptin infusion in lean and obese mice., Proc Natl Acad Sci USA source

In the paper

“Amylin is a peptide hormone secreted from pancreatic b cells that has a number of effects on plasma glucose that are synergistic with insulin.”

What the sources say

• Not checked yetcites [48] Roth, 2008, Leptin responsiveness restored by amylin agonism in diet-induced obesity: evidence from nonclinical and clinical studies., Proc Natl Acad Sci USA source

In the paper

“It is now known that the leptin receptor also signals at other central nervous system sites outside the hypothalamus and that its expression at these sites contributes to the broad panoply of leptin's effects (see below).”

In the paper

“The clinical significance of these findings was also assessed in humans in which the combination of leptin and amylin resulted in a substantial weight loss of 12.9%, which was significantly greater than that of either agent alone (48).”

What the sources say

• Not checked yetcites [48] Roth, 2008, Leptin responsiveness restored by amylin agonism in diet-induced obesity: evidence from nonclinical and clinical studies., Proc Natl Acad Sci USA source

In the paper

“The data further suggested that there was true synergy between leptin and amylin and that amylin could restore leptin signal transduction in the hypothalamus of DIO (diet-induced obesity) rats.”

What the sources say

• Not checked yetcites [48] Roth, 2008, Leptin responsiveness restored by amylin agonism in diet-induced obesity: evidence from nonclinical and clinical studies., Proc Natl Acad Sci USA source

In the paper

“Although leptin has been shown to have potent weight-reducing effects in obese animals with low leptin concentrations, this possibility has not been directly tested in humans (43).”

What the sources say

• Not checked yetcites [43] Ioffe, 1998, Abnormal regulation of the leptin gene in the pathogenesis of obesity., Proc Natl Acad Sci USA source

In the paper

“Leptin acts by modulating the activity of a set of neural pathways and, in general, activates pathways that inhibit food intake and inhibits pathways that activate food intake.”

In the paper

“A portion of leptin's actions appear to result from inhibition of neuropeptide Y/Agouti gene-related peptide (NPY/AGRP)-expressing neurons in the arcuate nucleus of the hypothalamus.”

In the paper

“Consistent with this, twin studies and other approaches have established a substantial genetic basis for obesity with a heritability of 0.7-0.9, a level exceeded only by height (64).”

What the sources say

• Not checked yetcites [64] Stunkard, 1990, The body-mass index of twins who have been reared apart., N Engl J Med source

In the paper

“The NPY/AGRP neurons act to stimulate appetite.”

In the paper

“Normal individuals typically show this activity only in the starved state and do not show this response after eating.”

What the sources say

• Not checked yetcites [52] Farooqi, 2007, Leptin regulates striatal regions and human eating behavior., Science source
• Not checked yetcites [53] Baicy, 2007, Leptin replacement alters brain response to food cues in genetically leptin-deficient adults., Proc Natl Acad Sci USA source
• Not checked yetcites [54] Licinio, 2007, Effects of leptin on intake of specific micro- and macronutrients in a woman with leptin gene deficiency studied off and on leptin at stable body weight., Appetite source

In the paper

“Obese individuals on average earn less money than their no-better-qualified lean counterparts and are promoted less readily (65,66).”

What the sources say

• Not checked yetcites [65] Friedman, 2004, Modern science vs. the stigma of obesity., Nat Med source
• Not checked yetcites [66] Friedman, 2003, A war on obesity, not the obese., Science source