If you are 15 pounds overweight or underweight, your leptin signaling may be out of whack. After assessing your symptoms, a blood test to measure leptin levels can help your healthcare provider to confirm a diagnosis of leptin resistance. Since leptin levels rise and fall, multiple blood tests may be necessary.
Leptin resistance can be successfully treated with various therapeutic interventions, many of which are diet-related. Following a leptin diet is key to leptin resistance treatment and weight loss. It may be difficulty to control overeating until leptin levels stabilize and proper leptin signaling returns. Controlling the types of foods you eat is the first step, and controlling the amount of food you eat will become easier as you heal your leptin resistance.
There is an extremely rare condition called congenital leptin deficiency, which is a genetic condition in which the body cannot produce leptin. In the UK, there are only about four families affected by this genetic condition.
Absence of leptin makes the body think it does not have any fat whatsoever and this results in uncontrolled food intake and severe childhood obesity. In addition, leptin deficiency may cause delayed puberty and poor function of the immune system. This condition can be well treated by leptin injections, which cause dramatic weight loss. About Contact Events News. Search Search. You and Your Hormones.
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Iron Deficiency Anemia in Celiac Disease. World J Gastroenterol —8. Jackson CS, Strong R. Gastrointestinal Angiodysplasia: Diagnosis and Management. Gastrointest Endosc Clin N Am — Peyrin-Biroulet L, Lopez A. Component 1 included classic milestones of metabolic adaptation during starvation, such as amino acids and ketone bodies that their concentrations change with fasting but independent from treatment placebo or leptin Supplementary Fig. This shows that blocking hypoleptinemia does not prevent the shift from carbohydrates to lipid utilization and ketone formation during starvation in lean humans.
Similarly, in study 2, sPLS-DA demonstrated changes with time during fasting component 2 consisting of ketone bodies, amino acids, and fatty acids but not with leptin dose Supplementary Fig. In line with the above findings, in study 4, long-term leptin administration did not induce any significant changes in amino acids, ketone bodies, or lipoproteins compared to placebo fatty acids were not assessed in this study, apart from free fatty acids FFA , which is indicated by the lack of distinct clusters in sPLS-DA and the lack of significantly different parameters in one-way ANOVA Fig.
Increasing color intensity indicates more time days of fasting. Increasing color intensity of symbol indicates more time weeks of study.
The observed major overlap between groups suggests no significant differences between placebo and leptin. Right: Evaluation of metabolites and lipoproteins with one-way ANOVA in placebo and leptin-treated subjects for up to 36 weeks. NMR-based metabolomics were used to quantify amino acids, metabolites, and lipids bound to lipoproteins. For metabolite nomenclature, see Supplementary Data 2. Regarding the lipid profile, when we assessed explicitly the concentrations of FFA Fig.
Interestingly, though component 3 consisting of ten parameters Fig. Indeed, the elevated concentrations of fatty acids both free and bound to lipoproteins are reduced partially to baseline level at the third day of placebo but not at the third day of leptin treatment Fig. This shows that blocking hypoleptinemia not only does not prevent the fasting-induced changes in lipid metabolism, but it may slightly stimulate them.
Blood FFA concentrations. P value of time effect i. Exact P values. In agreement with the mild stimulatory role of leptin on lipid catabolism during fasting, long-term leptin treatment in fed state led to a transient increase of the circulating levels of FFA.
In study 3, FFA was increased at day 15 of treatment and returned to baseline later Fig. Altogether, leptin treatment does not induce a major shift from carbohydrate to lipid utilization, but it may affect fatty acid profile, either by maintaining very high fatty acid levels during short-term treatment in acute fasting or by transiently increasing FFA during long-term treatment. Importantly, these findings justify a more in-depth lipidomic analysis in the future, that will include lipid subgroups that were not assessed in our current study.
Our results support the hypothesis that leptin demonstrates differential effects on energy regulation, depending on the metabolic context and energy balance 25 , 36 , as reflected by leptin levels, with a progressive loss of function from conditions of energy and leptin deficiency to conditions of energy and leptin excess.
Regarding body weight, short-term leptin treatment does not further induce the weight loss observed during acute fasting in lean individuals. The lack of effect of leptin can be both due to the short duration of treatment and due to the abolishment of the effects of leptin on energy intake through the imposed complete fasting.
Long-term leptin treatment in lean mildly hypoleptinemic women led to 4—4. However, blood leptin levels at baseline, which ranged between 1. This suggests that the response to leptin treatment in terms of weight loss may not depend linearly on the leptin blood concentrations, but may dependent on the metabolic context i.
Thus, defining strict thresholds in leptin blood concentrations as reliable predictors of weight loss with leptin treatment in obese populations may prove to be challenging and demands further studies in large populations with a wide range of leptin levels and different metabolic phenotypes. We now show that leptin treatment does not increase resting energy expenditure, does not stimulate physical activity, and does not affect markers of SNS activity HR, BP, cortisol, and catecholamine production in the lean normoleptinemic and partial hypoleptinemic individuals of our studies, supporting the rather marginal, if any, effects of leptin on energy expenditure in humans.
Third, both stimulatory and inhibitory effects of leptin on lipolysis and lipid utilization have been reported based on the metabolic context starvation or not , magnitude, and type of leptin deficiency CLD, GL, and PL and leptin dose. In rodents, starvation leads to hypoleptinemia and increased white adipose tissue WAT lipolysis via activation of the hypothalamic—pituitary—adrenal HPA axis 35 , Both WAT lipolysis and the activation of HPA are suppressed after physiologic leptin replacement, but stimulated after supraphysiologic leptin treatment In lean humans, a correlation between decreasing leptin levels and an increase in cortisol, FFA, and ketones during starvation was recently reported 34 , which suggested an anti-lipolytic role for leptin.
In our study, administration of leptin in lean individuals does not attenuate the amino acid surge or the robust increase observed in circulating FFA and ketone bodies with fasting even in very high leptin doses and does not significantly affect cortisol or catecholamine levels. On the contrary, we observe higher concentrations of total fatty acids during the third day of leptin treatment compared to placebo, which supports a stimulatory, if any, and not an inhibitory effect of leptin on lipid catabolism.
This is in agreement with observations in nonfasting conditions. In humans, similar to weight regulation, there is a progressive loss of the lipocatabolic effects of leptin from conditions of leptin deficiency to leptin excess. Consequently, in people with CLD, leptin replacement stimulates lipid catabolism lipolysis and oxidation as indicated by increases in ketone bodies, FFA, and acylcarnitines In people with GL or PL, leptin treatment has a modest effect on lipid catabolism, since it does not affect FFA and ketone body concentrations, but increases acylcarnitines and by-products of branched-chain amino acids and protein degradation Similarly, in our studies, leptin has a modest lipocatabolic effect in lean mildly hypoleptinemic women, as it is associated with a transient increase in FFA but no changes in ketone bodies or amino acid concentrations.
Importantly, the increase in FFA was not associated with alterations in hypothalamic—pituitary function and specifically with thyroid hormones or IGF-1, which are known to have lipolytic effects 53 , It was only associated with the reduction observed in aldosterone levels in study 3, which was not verified in study 4, where dose adjustments were performed to prevent too much body weight loss.
Given that aldosterone has rather lipolytic properties 55 , the transient, increased serum FFA may have an inhibitory effect on aldosterone secretion as a part of a compensatory mechanism. Similarly, in severe hypoleptinemic populations with CLD or GL, leptin decreases robust food intake by affecting hedonic and homeostatic nervous centers that control satiety and hunger feeling 31 , 57 , In lean women with mild acquired hypoleptinemia, leptin administration reduces salience, attention, and rewarding value of food In obese subjects after weight loss, which can be characterized as a condition of relative leptin deficiency, it affects brain activity and increases satiation 47 , In contrast, in obese—hyperleptinemic men, studied at their usual weight, leptin administration has minimal effects on appetite regulation In our studies, leptin administration in normoleptinemic lean subjects during short-term fasting partially prevents the increase of food intake at refeeding.
Thus, it is plausible to expect similar effects on energy intake in partially hypoleptinemic individuals under long-term leptin treatment, considering the similar impacts on body weight in our longer-term trials. Indeed, the projection curve for the expected fat mass loss due to reduced energy intake almost overlaps the real curve of fat mass loss observed in study 3, where leptin dose was not adjusted based on body weight changes.
In summary, we present herein that one of the main metabolic effects of leptin in lean subjects is the regulation of energy intake, an effect that is saturable as leptin increases to within physiological levels at least during refeeding after food deprivation.
This can be translated into weight loss, mainly due to fat mass loss, in the long term in subjects with chronic mild hypoleptinemia. Additionally, leptin treatment may lead to a transient increase in circulating FFA, without affecting energy expenditure and SNS activity. Although the effects of leptin on weight regulation, energy intake, and lipid catabolism are progressively lost with progression from conditions of energy and leptin deficiency to conditions of energy and leptin excess, the response to leptin treatment in terms of weight loss may not depend linearly on the leptin blood concentrations prior to treatment initiation.
This study has some limitations. In short-term fasting studies, we measured RMR but not total or non-resting energy expenditure due to lack of metabolic chambers. Additionally, no weighted buffet meals to assess energy intake were performed longitudinally under long-term leptin replacement and this remains to be studied in detail in the future.
Physical activity was calculated using daily self-report diaries as a surrogate of exercise-induced energy expenditure and this is a validated method. Our metabolite—lipid—lipoprotein analysis, although lege artis, did not include all circulating lipids or metabolites, and did not describe lipid subgroups and individual lipid species that should be the focus of more in-depth studies in the future.
Additionally, whether the increase we observed in FFA in studies 3 and 4 is related to an upregulation of lipolysis, reduced lipogenesis or changes in re-esterification could not be addressed with certainty in the context of the current experimental setting. We also acknowledge that the sample size, especially in study 2, may have been small, resulting in increased type II error for some parameters.
Finally, conclusions about SNS activity derive from catecholamines, HR and BP levels, and not from pharmacological blockade that may be able to detect very small differences or heart rate variability measures, which we have reported in the past We utilized data and specimens from our previous studies to perform new measurements and analyses 26 , 27 , 28 , 29 , 30 Supplementary Table 2.
The secondary outcomes were changes in energy expenditure i. Written informed consent was obtained from all participants prior to inclusion in the study. The interval between admissions was at least 8 weeks to allow recovery of hematocrit, leptin levels, and body weight.
Each subject completed three studies i. During each fed or fasting study, subjects were admitted to the CRC the evening before study day 0. Ad libitum feeding was allowed starting at on the third study day and meals were weighed to obtain accurate measures of the calories ingested. Blood samples were obtained at — am on days 0, 1, 2, and 3. Urine collection was performed on day 2.
The doses of leptin were 0. Males and females were administered a single dose of 0. The results from these studies had previously been reported separately for men and women but are combined herein [ClinicalTrials. One normoleptinemic fed and one hypoleptinemic study fasting were performed at each of the three different doses of leptin, resulting in six visits in total.
Leptin metreleptin, supplied by Amgen, Inc. For males, fed studies were performed after the completion of all three fasting studies. For females, the first day of each fasting study was scheduled during the beginning of each follicular phase, and thus fed studies were conducted either in between or after the fasting studies. Subjects were admitted to the CRC the night before the first study day and received a standardized kcal snack at After that, subjects fasted until of day 3 when they received a standardized kcal snack.
The interval between admissions was no less than 2 weeks. Subjects were admitted to the CRC the night before the study day. Each admission was separated by 1—12 weeks. Eight subjects received the 0. Vital signs, including HR, BP, body temperature, and respiratory rate, were measured at , , and — of each study day e.
Body weight was measured on the morning of each study day, prior to blood sampling and prior to breakfast regarding the fed admissions, with the same scale in CRC and with subjects dressed in a standard hospital gown. Leptin was administered at every morning. Finally, urine catecholamines were measured at baseline and on day 3 of each admission at the fasting state. Renin, aldosterone, and urine catecholamine measurements were not available in the fed state [ClinicalTrials.
Finally, all participants had normal prolactin and thyrotropin levels, ratios of luteinizing hormone LH to follicle-stimulating hormone FSH of more than 1. Subjects received leptin 0. Subjects who had not ovulated in the first 2 months continued with a third month of treatment at an increased dose of 0. Blood samples were obtained weekly and body composition was determined with dual-energy X-ray absorptiometry DEXA every other week, starting 1 month before initiation of leptin treatment baseline month, where measurements were performed at the beginning and end of the month.
Morning vital signs HR, BP, and temperature were obtained in the morning during baseline month and after 15 days of leptin treatment. Daily exercise records were obtained. Metabolic equivalent values used were according to the Compendium of Physical Activities Supplementary Table 3 Even though eight females were initially enrolled, one subject withdrew after 1 month for reasons unrelated to the study, and thus, the results are derived from the remaining seven subjects Fig.
All subjects were otherwise healthy, without active eating disorders or other psychiatric disease and were not taking any medications that could affect hormone or bone mass measurements i. Subjects were randomized with a allocation to receive either metreleptin or placebo for 36 weeks Randomization tables were produced by the Harvard Catalyst biostatisticians with SAS and delivered directly to the Research Pharmacy for use such that study staff that recruited subjects medical doctors, care providers as well as the participants would remain blinded.
Primary and secondary outcomes of the study were the difference between the placebo- and leptin-treated group for bone mineral content, bone markers, and bone mineral density, as well as reproductive outcomes from baseline to 36 weeks. Metreleptin was self-injected subcutaneously once daily at a dose of 0. The dose for subjects who had not menstruated at week 12 was increased to 0.
Fasting blood samples were collected every 4 weeks, along with fasting vital signs HR, BP, and temperature and body weight measurements. Physical activity was calculated as described for study 3. One participant in the metreleptin-treated group withdrew from the study because she developed injection-site reactions soon after the baseline visit, leaving 10 in the metreleptin group and 9 in the placebo group Fig.
FFA intra-assay variability: 1. Aldosterone intra-assay CV 1. High-throughput proton NMR metabolomics Nightingale Health Ltd, Helsinki, Finland was used to quantify circulating metabolites and lipids within lipoprotein particles. This is a targeted metabolomics approach where all metabolic measures are of known identity and therefore are in level 1 identification level according to Summer et al. The method leads to simultaneous quantification of lipoprotein subclasses with lipid concentrations, fatty acids, amino acids, ketone bodies, and metabolites related to gluconeogenesis Nightingale Health biomarker quantification library Details of the experimentation and proton NMR spectrometer characteristics have been described previously 65 , 66 , The resulting solution is then mixed by aspirating three times.
The latter is placed on top of the superconducting magnet inside which the NMR probehead is located. The sample is then kept idle inside the NMR probehead to achieve temperature stabilization at Thus, the measurement temperature is constant.
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