❖ MOTS-c is a 16-amino-acid peptide encoded in the mitochondrial genome.
❖ Sequence: Met-Arg-Trp-Gln-Glu-Met-Gly-Tyr-Leu-Phe-Tyr-Pro-Arg-Lys-Leu-Arg
❖ MW: 2288.6 g/mol
❖ Molecular formula: C10H152N28O22S2

Description: (Description by International Peptide Society)
Mitochondrial-derived peptides (MDPs), encoded by mitochondrial DNA, play a cytoprotective role by helping preserve mitochondrial function and cell viability under stressful conditions. MDPs signal within the cell or are released to act as autocrine/paracrine/endocrine cytoprotective factors and play a key role in the cellular stress response.

The MDP family includes human and SHLPs encoded from the 16S rRNA region and have broad protective effects and MOTS-c which is encoded from the 12S rRNA region and has metabolic signaling activity with potent anti-obesity effects. MDPs have been used clinically in various disease models and reported to play a role in many pathologies, including senolytic activity and delaying the progression of atherosclerosis, Alzheimer’s and chemotherapy-induced side-effects, supporting glucose/insulin regulation, weight management, and cardiovascular health, among other functions.

One of these MDPs, MOTS-c, holds great potential as a target to treat metabolic signaling issues by regulating muscle and fat physiology, and perhaps even extend a healthy lifespan.

MOTS-c is a 16-amino acid peptide encoded within the 12S rRNA region of mtDNA. It is measured in plasma and multiple tissues including muscle, brain, and liver. MOTS-c levels are correlated with insulin resistance in lean, not obese, individuals, and circulating MOTS-c levels are reduced in obese male children and adolescents, but not in obese females. MOTS-c is also involved in lung, bone, and cardiovascular disease.

Metabolic Signaling/ Insulin Sensitivity

MOTS-c bottom line is it helps turn available glucose into energy in the mitochondria. MOTS-c dramatically increases endogenous 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) levels and activates 5′ AMP-activated protein kinase (AMPK). MOTS-c increases glucose utilization, and fatty acid oxidation, and alters mitochondrial function and nucleotide metabolism. MOTS-c has been reported to target the skeletal muscle and enhance glucose metabolism.

MOTS-c levels are correlated with markers of insulin resistance and obesity including BMI, waist circumference, waist-to-hip ratio, fasting insulin level, HOMA-IR, and HbA1c. In addition, MOTS-c levels are correlated with endothelial function in humans. The effects of MOTS-c include:
❖ Increased glucose utilization and fatty acid oxidation
❖ Decreased oxidative phosphorylation
❖ Increased endogenous AICAR levels
❖ AMPK activation
❖ Increased glucose uptake into muscle cells

In laboratory studies, MOTS-c administration in high-fat diet-fed mice decreases weight gain by increasing energy expenditure and significantly decreases fat accumulation in the liver. The levels of insulin also were lower in MOTS-c–injected mice, suggesting that MOTS-c improves insulin sensitivity in high-fat diet-induced mice.
MOTS-c is reported to increase adipose thermogenic activation to promote cold adaptation. MOTS-c is reported to dramatically upregulate brown adipose tissue (BAT) thermogenic gene expression and increase white fat “browning”, probably mediated by activated phosphorylation of the ERK signaling pathway by MOTS-c.

MOTS-c is reported as a potential biomarker for metabolic function. As discussed earlier, MOTS-c levels are inversely correlated with markers of insulin resistance and obesity.

Aging and Longevity:
MOTS-c levels decline with age. Mitochondria are strongly implicated in aging and age-related diseases, and with the promising research and potential beneficial effects of MOTS-c in regulating metabolic homeostasis, the therapeutic implications in obesity and diabetes are evident.

There are metabolic links between known age modifiers and MOTS-c. NAD+ is a key metabolic coenzyme involved in redox reactions that decline with age, and restoring its levels can improve age-related disease conditions. Further, NAD+ is a potent activator of sirtuins, which are conserved multifunctional regulators of aging and age-related diseases in various model organisms from yeast to mammals. MOTS-c is reported to increase intracellular NAD+ levels and MOTS-c-dependent glycolytic effects are mediated by sirtuin 1 (SIRT1).

In addition, MOTS-c restricts the folate/methionine cycle, causing a reduction in methionine metabolism. This leads to a depletion of intracellular 5MTHF, increased levels of AICAR, and activation of AMPK in the presence of ATP accumulation and decreased mitochondrial respiration. It also may lead to increased homocysteine levels and folate depletion. In rodents, methionine restriction can increase lifespan by about 45%, decrease age-related diseases (such as cancer and type 2 diabetes), delay lens deterioration, reduce visceral fat, and increase the major antioxidant glutathione (GSH). Note this regulation of the folate-AICAR-AMPK pathway is similar to the drug methotrexate.

MOTS-c: Mitochondrial-encoded regulator of metabolic homeostasis

Mitochondria are key bioenergetics sources that fuel skeletal muscle during exercise, but they are also actively engaged in transmitting exercise-induced signals to other organs. Although the effect of exercise on regulating MOTS-c production and secretion is unknown, its beneficial effects on a high-fat diet (HFD) are mirrored by MOTS-c. As discussed earlier, MOTS-c increases cellular levels of AICAR (an AMPK agonist) and activates AMPK, a well-described regulator of exercise. In laboratory studies, MOTS-c injections were reported to activate mouse skeletal muscle AMPK and increase the level of the downstream glucose transporter GLUT4. MOTS-c may also act as a potential mitochondrial signal that mediates an exercise-induced mitohormesis response, thereby stimulating physiological adaptation and increased tolerance to exercise.

MOTS-c Promotes Metabolic Homeostasis

Cardiovascular Health
Aging, hyperlipidemia, insulin resistance, and atherosclerosis are all risk factors for cardiovascular diseases. MOTS-c is reported to protect against coronary endothelial dysfunction by the reduction of the release of pro-inflammatory cytokines and adhesion molecules, which results from the inhibition of NF-κB. MOTS-c is also involved in lipid metabolism. MOTS-c improves lipid utilization by stimulating carnitine shuttles to increase the level of β-oxidation. Moreover, MOTS-c can also reduce HFD-induced visceral fat accumulation and hepatic steatosis, but it is unclear whether this is due to decreased lipogenesis or increased lipolysis. In vitro, MOTS-c reduces triglyceride content, promotes AKT activity, and reduces lipid droplet deposition through the AMPK pathway in adipocytes. Although the genes associated with lipid oxidation did not change, the genes related to lipogenesis were significantly inhibited by MOTS-c treatment.

Studies also report MDPs to play a protective role in myocardial ischemia-reperfusion injury. A laboratory study reported MOTS-c attenuated vascular calcification and secondary myocardial remodeling by activating the adenosine monophosphate-activated protein kinase signaling pathway (AMPK) and suppressing the expression of the angiotensin II type 1 (AT-1) and endothelin B (ET-B) receptors.

Osteoporosis Prevention/Treatment
MOTS-c is reported to play a role in the synthesis of type 1 collagen by osteoblasts in bone tissue. MOTS-c is reported to suppress ovariectomy-induced osteoporosis via AMPK activation and improve osteoporosis via the TGF-βeta/SMAD pathway. MOTS-c also inhibits osteolysis by affecting osteocyte-osteoclast crosstalk and inhibiting inflammation in laboratory studies.

MOTS-c Osteolysis Inhibition

❖ Assists in mitochondrial biogenesis
❖ Activates AMPK
❖ Restores homeostasis by initiating a catabolic process for ATP production
❖ Decreases insulin resistance
❖ Increases GLUT4 uptake in muscle
❖ Improves athletic performance
❖ Improves weight loss

Clinical Pearls:
❖ This is an amazing peptide; an overall favorite
❖ The serum can be thick and sometimes there is some pruritus locally at the injection site for 5-15 minutes. We have our patients split the dose into two separate syringes; do ½ into one glute and ½ into the other to reduce the intensity of any local irritation.
❖ We follow a customary protocol of injecting once weekly for 4-6 weeks
❖ Always allow 2-3 months off in between uses

❖ Advitam Dosing: 10mg (split into two separate syringes) injected SubQ once weekly x 4-5 weeks
❖ Alternative dosing: 5mg injected SubQ 3x/wk x 4 wks

Safety/side effects:
❖ MOTS-c is reported safe in recommended dosages.
❖ Injection site pruritus.
❖ As with all injections, redness, and pain at the site of injection may be present.
❖ As MOTS-c targets the folate cycle and de novo purine biosynthesis pathways, it is possible a depletion of intracellular 5-methyl tetrahydrofolate (5-MTHF) may occur when using MOTS-c protocols. It may be advised to supplement the diet with folate as folinic acid or 5-MTHF, up to 1,200 mcg daily, between injections in the protocol, especially in those prone to folate deficiencies or methylation issues.
❖ It is recommended to check homocysteine and folate levels in patients taking MOTS-c.


Tesofensine (NS2330) is a serotonin–noradrenaline–dopamine reuptake inhibitor (SDNI) from the phenyltropane family of drugs, which is being developed for the treatment of obesity. It is also known as a triple reuptake inhibitor (TRI). Tesofensine was originally developed by a Danish biotechnology company, NeuroSearch, which transferred the rights to Saniona in 2014. As of 2019, tesofensine was discontinued for the treatment of Alzheimer's and Parkinson's disease and was subsequently dropped from development for these applications after early trial results showed limited efficacy for the treatment of these diseases. However, weight loss was consistently reported as an adverse event in the original studies, especially in overweight or obese patients. Therefore, it was decided to pursue the development of tesofensine for the treatment of obesity. It is currently in phase III clinical trials for obesity. It acts as an appetite suppressant and also acts by increasing resting energy expenditure.

❖ Tesofensine has a long half-life of about 9 days.
❖ Metabolized by P4503A4 (CYP3A4) to its desalkyl metabolite M1" NS2360.
❖ The NS2360 metabolite is detectable for 16 days.

❖ Indirectly potentiates cholinergic neurotransmission improving cognition, particularly in learning and memory.
❖ Sustained treatment with tesofensine has been shown to increase BDNF levels in the brain, and may possibly have an antidepressant effect.
❖ Weight loss
❖ Appetite suppression
❖ Increase in lean body mass
❖ Increased energy
❖ Promotes lipolysis
❖ Increases metabolism
❖ Improves sleep quality
❖ Decreased HA1C and insulin levels
❖ Decreased triglycerides and cholesterol

❖ 0.25mg capsule- Take one capsule PO qd
❖ 0.5mg capsule- Take one capsule PO qd
❖ 1.0mg capsule- Take one capsule PO qd

Side effects:
❖ Most common: dry mouth, headache, nausea, insomnia, diarrhea, constipation
❖ At the end of phase II trials Saniona concluded:
➢ Low incidence of increased heart rate, no significant effect on blood pressure