8. molecule acting on long term energy balance
• energy balance regulator : leptin and insulin
9. 2.1.1 leptin
• leptin secreted by white adipose tissue
• promote satiety and energy expenditure by stimulating POMC and inhibit NPY
in hypothalamus
• ↓leptin = hyperphagia and severe obesity
• obese = ↑leptin proportionally to body fat (leptin resistance)
10. 2.1.2 insulin
• secreted by pancreatic 𝛽-cells
• correlate with BW and adipose mass
• ↑insulin = ↓ reduced food intake
• obese = insulin resistance and hyperglycemia
• caused by ↑ FFA => hyperinsulinemia
• ↑carbs (esp. refined sugar) = ↑insulin secretion
• ↓carbs diet = ↑ energy energy expenditure = ↓BW
13. 2.2.1 neuropeptide Y
• NPY is
• most powerful feeding controller
• energy homeostasis regulation
• highly expressed in CNS
• NPY produced in
• arcuate nucleus
• most potent short-term stimulus for appetite
• neuron of SNS
• induce VC and fat tissue expansion
• negative energy balance = ↑of hypothalamic NPY = trigger ↑food
intake
14. 2.2.2 agouti related peptide
• agRP activated in condition of negative energy balance (ex:fasting)
• char: ↓plasma concentration of leptin and insulin = AgRP is inhibited
• selective AgRP neuron activation elicit hyperphagia to counteract the
state of metabolic need
• this activation shift the energy balance by
• stimulating rewarding mechanism associated with food
15. 2.2.3 ghrelin
• reaches highest plasma during fasting and immediately before meals
• synthesized by cells located in GI tract
• highest density in fundus of stomach
• in arcuate nucleus of hypothalamus
• ghrelin activate NPY and AgRP > stimulate appetite
• ghrelin in cancer with anorexia = increase energy intake
16. 2.2.4. endocannabinoid
• cannabis (cannabis sativa) effects = increased appetite
• ECS (endocannabinoid system) govern:
• appetite
• ingestive behavior
• energy metabolism
• body weight
• 2 receptor
• CB1 = distributed throughout brain (prim: hypothalamus and limbic system)
• involve in regulation of food intake and rewarding capacity
• CB2 = present in immune cells
• CB1 antagonist (rimonabant) in rats
• activate:
• lipid mobilization pathway in white adipose tissue
• cellular glucose uptake
• reduce food intake and BW
17. 2.3 Molecules Leading to Short-Term Negative
Energy Balance–Anorexigenic Stimuli
1. Secretin
2. Cholecystokinin
3. Incretin Hormones
4. Oxyntomodulin
5. Polypeptide Fold (PP-Fold) Family
6. Amylin
7. Cocaine- and Amphetamine-Regulated Transcript
18. .1. Secretin
• peptida asam amino 27
• diproduksi oleh sel-S di duodenum
• untuk sekresi bikarbonat di pancreas
• Dalam sirkulasi sekretin, makanan meningkatkan aktivasi
termogenesis jaringan adiposa coklat dengan merangsang
lipolisis melalui pengikatan pada reseptor sekretin dalam
adiposit coklat, memberikan sinyal di otak sehingga
meningkatkan rasa kenyang.
19. 2. Cholecystokinin (CCK)
• prototipe hormon kenyang yang diproduksi oleh sel enteroendokrin mukosa duodenum
dan jejunum, neuron dari sistem saraf enterik, dan otak
• Sekresi CCK dirangsang oleh adanya makanan di lumen usus
• CCK mengaktifkan neuron aferen vagal yang menyampaikan sinyal gastrointestinal ke
area otak belakang ( hind brain area), termasuk nukleus saluran soliter parabrachial
nucleus pusat regulasi pengaturan makan
• Sekresi CCK atau glucagon-like peptide 1 (GLP-1) mengaktikan calcium gene-related peptide
(CGRPPBN) pada parabrachial nucleus yang mengepresikan penghentian makan
• Jika neuron AgRP hipotalamus menghambat neuron CGRPPBN ,maka stimulasi AgRP akan
menimbulkan rasa untuk makan
20. 3. Incretin Hormones
• peptida yang disekresikan oleh sel entero-endokrin sebagai respons
terhadap asupan makanan yang menyebabkan stimulasi sekresi
insulin.
• Hormon inkretin yang dikenal adalah GIP (glucose-dependent
insulinotropic polypeptide) dan GLP-1 (glucagon-like peptide-1)
• GIP merangsang sekresi glucagon, dapat menyebabkan
peningkatan transpor glukosa yang distimulasi insulin, sintesis asam
lemak, dan trigiserida
• GLP-1 menekan sekresi glukagon , pengurangan nafsu makan dan
asupan makanan, yang menyebabkan penurunan berat badan
dalam jangka panjang
21. 4. Oxyntomodulin
• OXM dilepaskan dari sel entero-endokrin sebagai respons
terhadap nutrisi dalam bentuk asam lemak bebas dan karbohidrat.
• OXM mengaktifkan glucagon like peptide-1 receptor (GLP1R) dan
glucagon receptor (GCGR) yang menghasilkan pengurangan
asupan makanan dan peningkatan pengeluaran energi
• GLP1 terutama merangsang area di batang otak
• OXM bekerja pada nukleus arkuata
• meningkatkan sekresi insulin secara signifikan dan menurunkan
kadar glukosa bahkan pada pasien diabetes tipe 2
22. 5. Polypeptide Fold (PP-Fold) Family
• terdiri dari neuropeptida Y (NPY), peptida tirosin tirosin (PYY), dan
polipeptida pankreas (PP)
• empat subtipe reseptor berpasangan G-protein (Y1, Y2, Y4, Y5)
• PYY terutama diproduksi oleh sel L enteroendokrin usus ,
PP disintesis oleh sel F endokrin dari pulau pankreas
• Pelepasan PP dan PYY menghasilkan penghambatan jalur
anoreksigenik hipotalamus.
• PYY bertindak melalui reseptor Y2 dan menghambat pelepasan NPY
di nukleus arkuata
• PP mengaktifkan jalur kolinergik vagal di batang otak melalui
reseptor Y4 , PP mengurangi nafsu makan dan asupan makanan
23. 6. Amylin
• disekresikan oleh sel ÿ pankreas dan dilepaskan bersama
dengan insulin
• diekspresikan di hipotalamus lateral secara sinergis dengan
leptin
• meningkatkan pengeluaran energi
• memediasi efek kenyang, meningkatkan cGMP dan
memfosforilasi ERK sinyal yang memicu efek anoreksia.
24. 7. Cocaine- and Amphetamine-Regulated
Transcript (CART)
• berperan dalam regulasi neuroendokrin dan regulasi otonom,
mengontrol fungsi fisiologis dan perilaku, serta penghambatan
makan dan stimulasi anxietas
25. 2.4. Molekul Sekresi Jaringan Adiposa Putih
(White Adipose Tissue Secreted Molecules )
• Adipokin berperan dalam modulasi makan, metabolisme
glukosa dan lipid, atau fungsi inflamasi dan kekebalan tubuh .
• Sensitivitas insulin ditingkatkan terutama dimediasi oleh
adiponektin adalah hasil dari peningkatan oksidasi
asam lemak dan menekan produksi glukosa hati.
• fungsi utama adiponektin adalah perifer, adiponektin
dan leptin memiliki aksi sinergis pada otak dan keduanya
mendorong penurunan berat badan.
• leptin menghambat nafsu makan, adiponektin meningkatkan
pengeluaran energi.
26. 2.5. Molekul yang Disekresikan Jaringan
Adiposa Coklat (BAT)
• memiliki peran dalam thermogenesis non-menggigil.
• Manfaat peningkatan jaringan adiposa coklat untuk
meningkatkan pengeluaran energi, mengurangi berat badan
atau mengurangi resistensi insulin
• faktor yang disekresikan oleh jaringan adiposa
coklat, yang disebut adipokin coklat atau BATokines, dalam
mengatur metabolisme sistemik
27. Saat ini ada enam obat anti-obesitas utama yang disetujui oleh Amerika Serikat
Food and Drug Administration (FDA)
28.
29. Orlistat
Efficacy: Orlistat is indicated in conjunction with a reduced-calorie diet
for patients with a BMI ≥ 30 kg/m2 or ≥ 28 kg/m2 with comorbidities
like hypertension, diabetes, hyperlipidemia
Safety: Gastrointestinal side effects, reduced absorption of fat-soluble
vitamins and steatorrhea are very frequent.
Clinical insight: Orlistat 120 mg is administered three times daily.
30. Liraglutide
• Efficacy: The efficacy of 3.0 mg liraglutide in combination with a
reduced-calorie diet and increased physical activity was assessed in
four 56-week randomized, placebo controlled trials . A meta-analysis
noted an additional annual weight loss of 5.3–5.9 kg compared to
placebo .
• Safety: Most common side effects are transient and mild to moderate
intensity gastrointestinal symptoms like: nausea, diarrhea,
constipation, vomiting, dyspepsia, and abdominal.
• Clinical insight: The initial dose is 0.6 mg subcutaneously once daily
for the first week followed by 0.6 mg increments every week, to a
maximum of 3.0 mg.
31. Naltrexone/Bupropion
opiate antagonist, which blocks opioid receptor-mediated POMC
auto-inhibition, whilst bupropion selectively inhibits reuptake of dopamine and
noradrenaline
Sherman, M.M.; Ungureanu, S.; Rey, J.A. Naltrexone/bupropion ER (Contrave): Newly approved treatment option f
weight management in obese adults.
32. The combination therapy is approved since 2012 by
both the FDA and EMA
The combination promotes satiety via enhancement of
hypothalamic POMC-mediated release of melanocyte-
stimulating hormone (MSH) resulting in reduced food
intake and increased energy expenditure
33. Singh, A.K.; Singh, R. Pharmacotherapy in obesity: A systematic review and meta-analysis of randomized controlle
anti-obesity drugs. Expert Rev. Clin. Pharmacol. 2020, 13, 53–64.
A meta-analysis reported an annual weight loss of 4.8%
total body weight (mean 4.4 kg)
34. Clinical insight:
The current naltrexone SR/bupropion SR combination is available in 8 mg
naltrexone SR and 90 mg bupropion dosing, which is upwards titrated over a 4-
week period for a total dosage of two tablets twice daily: one tablet once daily in
the morning during week 1, one tablet twice daily during week 2, two tablets in
the morning and one tablet in the evening during week 3, and finally two tablets
twice daily during week 4 [172].
During the initial stage, if significant adverse effects occur, the dose should not
be further escalated until better tolerability is established. If within 12 weeks
less than 5% of initial body weight is lost the drug should be discontinued.
Naltrexone SR/bupropion
SR appears to have good effects in patients with food addiction [177] and
binge-eating disorder concomitant with alcohol abuse
35. Tak, Y.J., Lee, S.Y. Long-Term Efficacy and Safety of Anti-Obesity Treatment: Where Do We Stand?. Curr Obes Rep 10, 14–30
(2021). https://doi.org/10.1007/s13679-020-00422-w
Figure 1. Central mechanisms of anti-obesity drugs
36. Front. Endocrinol., 24 August 2021 Sec. Cellular Endocrino
https://doi.org/10.3389/fendo.2021.722441
FIGURE 2 Peripheral mechanisms of anti-obesity drugs
37. Diethylpropion
an amphetamine derivative and a sympathomimetic stimulant with anti-obesity
and appetite-suppressant properties
Gjermeni E, Kirstein AS, Kolbig F, Kirchhof M, Bundalian L, Katzmann JL, Laufs U, Blüher M, Garten A, Le Duc D. Obesity-An
Update on the Basic Pathophysiology and Review of Recent Therapeutic Advances. Biomolecules. 2021 Sep 29;11(10):1426. doi:
10.3390/biom11101426. PMID: 34680059; PMCID: PMC8533625.
38. Setmelanotide
MC4R agonist, which acts in the paraventricular nucleus of
the hypothalamus and in the lateral hypothalamic area to suppress the appetite
Gjermeni E, Kirstein AS, Kolbig F, Kirchhof M, Bundalian L, Katzmann JL, Laufs U, Blüher M, Garten A, Le Duc D. Obesity-An
Update on the Basic Pathophysiology and Review of Recent Therapeutic Advances. Biomolecules. 2021 Sep 29;11(10):1426. doi:
10.3390/biom11101426. PMID: 34680059; PMCID: PMC8533625.
FDA
(Novembe
r 2020)
FDA Approves First Treatment for Weight Management for People with Certain Rare Genetic Conditions|FDA. Available
online: https://www.fda.gov/drugs/drug-safety-and-availability/fda-approves-first-treatment-weight-management-peoplecertain-
rare-genetic-conditions (accessed on 6 August 2021).
40. IMCIVREE [prescribing information]. Boston, MA. Rhythm Pharmaceuticals, Inc. 2. Eneli I et al. Appl Clin Genet. 2019;12:87-
93. 3. Huvenne H et al. Obes Facts. 2016;9(3):158-173. 4. Seo S et al. Hum Mol Genet. 2009;18(7):1323-1331. 5. Forsythe E,
Beales PL. Eur J Hum Genet. 2013;21(1):8-13. 6. National Institutes of Health. MedlinePlus® Genetics. Accessed May 3, 2022.
https://medlineplus.gov/genetics/condition/bardet-biedl-syndrome/#inheritance.
IMCIVREE is indicated for chronic weight management in adul
and pediatric patients 6 years of age and older with monogenic
or syndromic obesity due to Bardet-Biedl syndrome (BBS).
https://www.imcivree.com/hcp/bbs/dosing-administration/
FIGURE 4. The MC4R pathway is a key signaling pathway that
regulates hunger, satiety, and energy expenditure
FIGURE 5. IMCIVREE, an MC4R agonist, is designed
to re-establish MC4R pathway activity
FIGURE 6. 10-mg/1-Ml
multiple-dose vial
41. subcutaneously
with a starting
dose
of 2 mg/day for two weeks. If
the initial dose is not tolerated,
the dose should be reduced
titrated to 3 mg/day. If weight loss is
not 5% of baseline body weight after
12–16 weeksof treatment, the
administration should be discontinued.
to half till the desired
tolerability is achieved. If
the initial dose is well
tolerated it can be
Gjermeni E, Kirstein AS, Kolbig F, Kirchhof M, Bundalian L, Katzmann JL, Laufs U, Blüher M, Garten A, Le Duc D. Obesity-An
Update on the Basic Pathophysiology and Review of Recent Therapeutic Advances. Biomolecules. 2021 Sep 29;11(10):1426. doi:
10.3390/biom11101426. PMID: 34680059; PMCID: PMC8533625.
Clinical insight
FIGURE 6. 10-mg/1-Ml
multiple-dose vial
42. semaglutide
GLP1 receptor agonist with similar mechanism of action
the most recently approved anti-
obesity drug
Gjermeni E, Kirstein AS, Kolbig F, Kirchhof M, Bundalian L, Katzmann JL, Laufs U, Blüher M, Garten A, Le Duc D. Obesity-An
Update on the Basic Pathophysiology and Review of Recent Therapeutic Advances. Biomolecules. 2021 Sep 29;11(10):1426. doi:
10.3390/biom11101426. PMID: 34680059; PMCID: PMC8533625.
43. Rubino, D.; Abrahamsson, N.; Davies, M.; Hesse, D.; Greenway, F.L.; Jensen, C.; Lingvay, I.; Mosenzon, O.; Rosenstock, J.;
Rubio,
M.A.; et al. Effect of Continued Weekly Subcutaneous Semaglutide vs Placebo on Weight Loss Maintenance in Adults With
Overweight or Obesity. JAMA 2021, 325, 1414.
double-blind trial,
1961 adults with a body-mass index 30 or greater
68 weeks of treatment
with once-weekly subcutaneous semaglutide (at a dose
of 2.4 mg) or placebo,
Plus lifestyle intervention
44. Rubino, D.; Abrahamsson, N.; Davies, M.; Hesse, D.; Greenway, F.L.; Jensen, C.; Lingvay, I.; Mosenzon, O.;
Rosenstock, J.; Rubio, M.A.; et al. Effect of Continued Weekly Subcutaneous Semaglutide vs Placebo on
Weight Loss Maintenance in Adults With Overweight or Obesity. JAMA 2021, 325, 1414.
In participants with overweight or obesity, 2.4
mg of semaglutide once weekly plus lifestyle
intervention was associated with sustained,
clinically relevant reduction in body weight.
(Funded by Novo Nordisk; STEP 1
ClinicalTrials.gov number, NCT03548935).
45. Arastu N, Cummins O, Uribe W, Nemec EC. Efficacy of subcutaneous semaglutide compared to placebo for weight loss in obese,
non-diabetic adults: a systematic review & meta-analysis. Int J Clin Pharm. 2022 Aug;44(4):852-859. doi: 10.1007/s11096-022-
01428-1. Epub 2022 Jun 17. PMID: 35715543.
332 relevant articles,
Random controlled trials
2882 participants BMI ≥ 27 kg/m2
SIGNIFICANT REDUCTION in MEAN BODY WEIGHT
- 11.62 kg (95% CI:-13.03 to -10.21; P < 0.00001).
46. Meier JJ. Efficacy of Semaglutide in a Subcutaneous and an Oral Formulation. Front Endocrinol (Lausanne). 2021 Jun 25;12:645617. doi:
10.3389/fendo.2021.645617. PMID: 34248838; PMCID: PMC8269445.
Efficacy of Semaglutide in a Subcutaneous and an Oral Formulation
47. Gjermeni E, Kirstein AS, Kolbig F, Kirchhof M, Bundalian L, Katzmann JL, Laufs U, Blüher M, Garten A, Le Duc D. Obesity-An
Update on the Basic Pathophysiology and Review of Recent Therapeutic Advances. Biomolecules. 2021 Sep 29;11(10):1426. doi:
10.3390/biom11101426. PMID: 34680059; PMCID: PMC8533625.
https://emedz.net/rybelsus-ozempic-semaglutide
Clinical insight
once weekly, initiated at 0.25 mg, with
dose escalation every 4 weeks to 0.5 mg, 1 mg, 1.7
mg until the target dose of 2.4 mg/week is reached.
If participants cannot tolerate the 2.4-mg dose, they
can receive 1.7 mg instead.
They should be encouraged to make at least 1 attempt
to re-escalate to the 2.4-mg dose.
FIGURE 9. Injectable &
Oral Semaglutide
48. Lorcaserin
is a 5-hydroxytryptamine receptor 2C (5-HT2c) agonist that acts on anorexigenic
POMC neurons in the hypothalamus to suppress the appetite
Withdrawn from Market in
February 2020
Gjermeni E, Kirstein AS, Kolbig F, Kirchhof M, Bundalian L, Katzmann JL, Laufs U, Blüher M, Garten A, Le Duc D. Obesity-An
Update on the Basic Pathophysiology and Review of Recent Therapeutic Advances. Biomolecules. 2021 Sep 29;11(10):1426. doi:
10.3390/biom11101426. PMID: 34680059; PMCID: PMC8533625.
49. adults with a
BMI 30 kg/m2
or those with
a BMI 27
kg/m2
diabetes,
hypertension,
hyperlipidemia
or sleep
apnoea
Gjermeni E, Kirstein AS, Kolbig F, Kirchhof M, Bundalian L, Katzmann JL, Laufs U, Blüher M, Garten A, Le Duc D. Obesity-An
Update on the Basic Pathophysiology and Review of Recent Therapeutic Advances. Biomolecules. 2021 Sep 29;11(10):1426. doi:
10.3390/biom11101426. PMID: 34680059; PMCID: PMC8533625.
Singh, A.K.; Singh, R. Pharmacotherapy in obesity: A systematic review and meta-analysis of randomized controlled trials of
anti-obesity drugs. Expert Rev. Clin. Pharmacol. 2020, 13, 53–64. [CrossRef]
a mean annual
weight loss of 3.1 kg
improved metabolic parameters like blood
pressure, total and LDL cholesterol
EMA did not approve the use of
lorcaserin
and FDA requested withdrawal from
market in February 2020 because of
possible increased risk of colorectal,
pancreatic, and lung cancer
51. Sadaf Farooqi,Treating obesity: Does antagonism of NPY fit the bill?,Cell Metabolism, Volume 4, Issue 4, 2006, Pages 260-262,
ISSN 1550-4131,https://doi.org/10.1016/j.cmet.2006.09.006.
FIGURE 2. Leptin acts on two distinct populations of neurons located in the
arcuate nucleus of the hypothalamus
52. metreleptin failed to achieve clinically
meaningful weight loss with a mean of just
1.5 kg lost over 24 weeks
a combination therapy with amylin
mimetics such as pramlintide was tested
with good results showing 11.5 kg
weight loss over 20 weeks compared with
7.4 kg and 7.9 kg for metreleptin or
pramlintidemonotherapy, respectively
Williams, D.M.; Nawaz, A.; Evans, M. Drug Therapy in Obesity: A Review of Current and Emerging Treatments. Diabe
2020, 11, 1199–1216.
Heymsfield, S.B.; Greenberg, A.S.; Fujioka, K.; Dixon, R.M.; Kushner, R.; Hunt, T.; Lubina, J.A.; Patane, J.; Self, B.; Hunt, P.; et al.
Recombinant Leptin for Weight Loss in Obese and Lean Adults. JAMA 1999, 282, 1568–1575.
Ravussin, E.; Smith, S.R.; Mitchell, J.A.; Shringarpure, R.; Shan, K.; Maier, H.; Koda, J.E.;Weyer, C. EnhancedWeight LossWith
Pramlintide/Metreleptin: An Integrated Neurohormonal Approach to Obesity Pharmacotherapy. Obesity 2009, 17, 1736–1743.
the further development of
the combination therapy was
discontinued in 2011
in 2014 FDA
approved the use of
metreleptin in patients
with leptin deficiency or
lipodystrophy as
subcutaneous injection in
a once or twice daily
administration
53. Perakakis N, Farr O, Mantzoros C, et al. Leptin in Leanness and Obesity. J Am Coll Cardiol. 2021 Feb, 77 (6) 745
760.https://doi.org/10.1016/j.jacc.2020.11.069
54. Perakakis N, Farr O, Mantzoros C, et al. Leptin in Leanness and Obesity. J Am Coll Cardiol. 2021 Feb, 77 (6) 745
760.https://doi.org/10.1016/j.jacc.2020.11.069
55. Perakakis N, Farr O, Mantzoros C, et al. Leptin in Leanness and Obesity. J Am Coll Cardiol. 2021 Feb, 77 (6) 745
760.https://doi.org/10.1016/j.jacc.2020.11.069
57. ghrelin antagonists showed no success in
human studies and clinical studies are
currently not undertaken
Williams, D.M.; Nawaz, A.; Evans, M. Drug Therapy in Obesity: A Review of Current and Emerging Treatments. Diabe
2020, 11, 1199–1216.
59. Christensen, R.; Kristensen, P.K.; Bartels, E.M.; Bliddal, H.; Astrup, A. Efficacy and safety
Sam, A.H.; Salem, V.; Ghatei, M.A. Rimonabant: From RIO to Ban. J. Obes. 2011, 2011, 432607. of the weight-loss drug
Rimonabant, a CB1 antagonist showed excellent
weight loss outcomes with an additional
mean weight loss of 4.7 kg in clinical trials
FIGURE 8. Potential mechanisms of action of rimonabant, a selective cannabinoid type-1 receptor (CB1 R)
antagonist, in the improvement of glucose control and other cardiometabolic risk factors in overweight/ obese
patients with type-2 diabetes.
in 2009, Rimonabant had to
be withdrawn because of the
increased risk of severe
mood disorders and suicide
60. NPY antagonists
Neuropeptide Y (NPY) is an orexigenic neuropeptide that plays a role in regulating adiposity by
promoting energy storage in white adipose tissue and inhibiting brown adipose tissue activation
in mammals.
61. NPY inhibition did not achieve
clinically meaningful results to
justify obesity treatment
Erondu, N.; Gantz, I.; Musser, B.; Suryawanshi, S.; Mallick, M.; Addy, C.; Cote, J.;
Bray, G.; Fujioka, K.; Bays, H.; et al. Neuropeptide Y5 receptor antagonism does
not induce clinically meaningful weight loss in overweight and obese adults. Cell.
Metab. 2006, 4, 275–282.
63. Pramlinetide licensed by the FDA in 2005
for patients with insulin-treated diabetes,
results with different analogues appeared
to be quite variable
Williams, D.M.; Nawaz, A.; Evans, M. Drug Therapy in Obesity: A Review of Current and Emerging Treatments. Diabe
2020, 11, 1199–1216.